Novel ppar ligands that do not cause fluid retention, edema or congestive heart failure

ABSTRACT

Methods are provided for treating or prophylactically preventing metabolic disorders in humans without causing, promoting, or aggravating fluid retention, peripheral edema, pulmonary edema, or congestive heart failure, by administration of a therapeutically effective amount of a compound sufficient to partially or fully activate peroxisome proliferator activated receptors (PPARs) and partially or fully inhibit, antagonize or block the activity of angiotensin II type 1 receptors. Metabolic disorders that can be treated or prevented include but are not limited to type 2 diabetes, the metabolic syndrome, prediabetes, and other insulin resistance syndromes. Compounds are provided that antagonize or block the angiotensin II type 1 (AT1) receptor, function as partial or full activators of peroxisome proliferator activated receptors (PPARs), can be used to treat or prevent diseases known to be treatable or preventable by PPAR activators and were not previously recognized to be therapeutic targets for angiotensin II receptor antagonists.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/796,453, filed on Apr. 27, 2007, which is a continuation of U.S.patent application Ser. No. 10/627,372, filed on Jul. 24, 2003 (nowissued as U.S. Pat. No. 7,232,828) and also claims the benefit of U.S.Provisional Application No. 60/402,425, filed Aug. 10, 2002 and U.S.Provisional Application No. 60/455,211, filed Mar. 15, 2003, each of thedisclosures of which are herein incorporated by reference in theirentirety.

TECHNICAL FIELD OF THE INVENTION

This invention relates to the field of prevention and treatment ofcardiovascular diseases and insulin resistance syndromes. Specifically,this invention relates to compounds that increase both the activity ofperoxisome proliferator activated receptors (PPARs) andblocks/antagonizes activity of the angiotensin II type 1 receptor. Morespecifically, this invention relates to novel clinical uses of certainangiotensin II type 1 receptor blockers (ARBs) which can increase theactivity of peroxisome proliferator activated receptors (PPARs).

BACKGROUND OF THE INVENTION

Peroxisome proliferator-activated receptors (PPARs) are members of thenuclear receptor superfamily of ligand-activated transcription factors.Three subtypes of PPARs have been cloned from the mouse and human: i.e.,PPARα, PPARγ, and PPARδ. The PPARs are important regulators ofcarbohydrate and lipid metabolism, cell growth and differentiation,phenotype transition, apoptosis, neovascularization, immunoregulationand the inflammatory response. Compounds that activate PPARs are usefulfor the treatment and prevention of a variety of clinical disordersincluding but not limited to the metabolic syndrome, obesity,pre-diabetes, type 2 diabetes, and other insulin resistant syndromes,hypertension, atherosclerosis, dyslipidemia, inflammatory skin diseasessuch as psoriasis, inflammatory bowel disease, and inflammatoryneurodegenerative diseases such as multiple sclerosis and Alzheimer'sdisease. The metabolic syndrome as referred to herein includes themetabolic syndrome as defined by either the World Health Organization(WHO) or the National Cholesterol Education Program (NCEP) (Zimmet P, etal. Global and societal implications of the diabetes epidemic. Nature.(2001) 414:782-7; Alberti K G, Zimmet P Z. Definition, diagnosis andclassification of diabetes mellitus and its complications. Part 1:diagnosis and classification of diabetes mellitus provisional report ofa WHO consultation. Diabet Med. (1998) 15:539-53; Executive Summary ofThe Third Report of The National Cholesterol Education Program (NCEP)Expert Panel on Detection, Evaluation, And Treatment of High BloodCholesterol In Adults (Adult Treatment Panel III). JAMA (2001)285:2486-97.).

Examples of known compounds that can activate PPARs includethiazolidinediones (e.g. rosiglitazone, pioglitazone, MK 767 (KRP-297),MCC-555, netoglitazone, balaglitazone, rivoglitazone) that primarilyactivate PPARgamma or PPARgamma and PPARalpha, andnon-thiazolidinediones that can activate any combination of PPARgamma,PPARalpha and PPARdelta (e,g, JTT-501, LSN862, DRF 4832, LM 4156, LY510929, LY 519818, TY 51501, X 334), certain tyrosine-based derivatives(e.g. GW1929, GW7845), phenylacetic acid-based derivatives, phenoxazinephenyl propanoic acid derivatives (e.g. DRF 2725, DRF 2189), cinammicand dihydrocinammic acid-based derivatives (e.g. tesaglitazar (AZ 242)),and 3-Phenyl-7-propylbenzisoxazoles (Adams A D, et al. Bioorg Med ChemLett. (2003) 13:931-5), that can activate PPARgamma in combination withPPARalpha or PPARdelta or both PPARalpha and PPARdelta. Althoughcompounds are available that may primarily activate PPARalpha alone orPPARdelta alone, it is common for such compounds to also cause at leastsome degree of PPARgamma activation as well.

Although drugs that activate PPARgamma have proven to be valuable forthe prevention and treatment of type 2 diabetes and a variety of otherdisorders, the currently available agents cause adverse effects oraggravate certain conditions that can limit the clinical utility andsafety of these ligands. Some of the principle limiting side effects orconditions that can be provoked or aggravated by both thiazolidinedioneand non-thiazolidinedione compounds that activate PPARgamma either aloneor in combination with other PPARs are fluid retention, peripheraledema, pulmonary edema, and congestive heart failure. Both rosiglitazoneand pioglitazone have received regulatory approval for the treatment oftype 2 diabetes in many countries including the United States andthroughout the European Community. The extensive accumulated experiencewith worldwide use of these drugs has revealed that thia{grave over(z)}olidinediones can cause fluid retention, which exacerbates or leadsto edema and/or congestive heart failure (CHF). Patients with ongoingedema are prone to adverse effects when on thiazolidinedione therapy,and especially if this is combined with administration with insulin,consisting of up to 16% of patients in the latter group. This ispotentially a serious problem, considering that among patients with type2 diabetes likely to be treated with thiazolidinediones or othernon-thiazolidinedione agonist, a significant percentage have CHF or areat high risk for developing CHF because of their high cardiovascularrisk profiles. Fluid retention caused by PPAR activators can not onlycause volume expansion and peripheral edema, but also can also induce oraggravate life-threatening conditions such as CHF and pulmonary edema.Therefore, there is considerable interest in identifying and usingPPARgamma activators that do not cause substantial fluid retention andtherefore do not increase the risk for edema and congestive heartfailure.

The current invention relates to the surprising discovery that certainARBs can increase the activity of PPARgamma and can be used to treat orprevent type 2 diabetes, the metabolic syndrome, and other disordersresponsive to PPAR activators or PPAR activation, without increasing therisk for fluid retention, peripheral edema, pulmonary edema, orcongestive heart failure. Although previous studies have shown that therisk for type 2 diabetes in patients given ARBs is lower than that inpatients given other antihypertensive drugs, it could not have beenpredicted that certain ARBs could be used to prevent or treat type 2diabetes, the metabolic syndrome or other disorders responsive to PPARligands.

It has been unclear whether ARBs actually decreased the risk fordiabetes or whether the drugs to which they were being comparedincreased the risk for diabetes. For example, the lower risk of diabetesreported in patients given ARBs versus beta blockers or thiazidediuretics was due to the fact that beta blockers and thiazide diureticsaggravate insulin resistance and therefore, the results of clinicalstudies comparing ARBs to other agents cannot be used to predict whetherARBs can be used to prevent or treat diabetes or other disordersresponsive to PPARgamma activators.

Several trials have investigated the effects of ARBs on glucosehomeostasis but the results are conflicting and controversial (for areview of this subject, see: Bernobich E, et al. Drugs (2002)62:1295-1314). There are no data available that consistently demonstratethat ARBs improve insulin sensitivity, attenuate insulin resistance, orcan be used to treat or prevent type 2 diabetes, the metabolic syndrome,or other insulin resistance syndromes. Expert opinions expressed in themedical and scientific literature hold that drugs that block angiotensinII type 1 receptors (ARBs) (also known as “sartans”) are “metabolicallyneutral” (Epstein M. Angiotensin II Receptor Antagonists: CurrentStatus. In: Angiotensin II Receptor Antagonists. Epstein M and Brunner HR (eds), Hanley & Belfus, Inc., Philadelphia, (2002) pp 257-261). Forexample, the ARB losartan has a neutral effect on glucose metabolism,insulin sensitivity, and serum concentrations in patients with mildhypertension (Bernobich E, et al. Drugs (2002) 62:1295-1314), and inclinical studies with diabetic patients, candesartan does notappreciably alter their hemoglobin Alc, glucose concentration or lipidprofile (Easthope S E, et al. Drugs 2002; 62:1253-87).

In a recent clinical trial (LIFE trial) where the ARB losartan wascompared to the β-blocker atenolol, the incidence of new-onset type 2diabetes was greater in the atenolol treated patients than in thosetreated with losartan (Dahlof B, et al. Lancet (2002) 359:995-1003).However, β-blockers like atenolol are known to be clinicallydiabetogenic and can promote or worsen insulin resistance and therebypromote the development of type 2 diabetes (Teuscher A U, et al. JHypertens Suppl. (1997) 15:S67-75). Therefore, the lower incidence ofnew-onset type 2 diabetes in the losartan arm of the study actuallyreflected an increase in the incidence of new-onset type 2 diabetes inthe atenolol arm. Studies showing a lower incidence of new onsetdiabetes in patients treated with the ARB candesartan compared topatients treated with thiazide diuretics also indicate that the ARBcandesartan did not decrease the risk for diabetes, rather, the thiazidediuretic increased the risk for diabetes. Consequently, the prior artcould not be used to predict that losartan, telmisartan, irbesartan, orany other ARB could be used to prevent or treat type 2 diabetes, themetabolic syndrome, or other forms of insulin resistance. Moreover,because the ARBs have important structural chemical differences, anyunusual or unexpected results obtained with one ARB cannot be used topredict that similar results would be obtained with another ARB.

In the obese Zucker rat, Henriksen et al. found that oral administrationof an extremely high dose of irbesartan improved insulin sensitivity butapparently failed to improve lipid levels (Henriksen E J, et al.Selective angiotensin II receptor antagonism reduces insulin resistancein obese Zucker rats. Hypertension. (2001) 38:884-90). However, theobese Zucker rat is an unusual form of obesity and insulin resistancethat is caused by mutations in the leptin receptor and furthermore, therats studied by Henriksen did not have type 2 diabetes. Mutations inleptin receptors in humans are extremely rare and almost never accountfor type 2 diabetes, obesity, insulin resistance, or the metabolicsyndrome in humans. Therefore, the studies by Henriksen et al. in whichan extremely high dose of irbesartan was found to improve insulinsensitivity in obese Zucker rats can not be used to predict or implythat irbesartan or any other ARB could be used to activate PPARγ in vivoor be used to treat or prevent type 2 diabetes, the metabolic syndrome,or other insulin resistance syndromes in humans.

In 2002, after the current discovery was made, Sharma and colleaguesreported that very high concentrations of angiotensin II can inhibitdifferentiation of human preadipocytes and that high concentrations ofirbesartan can enhance adipogenesis (Janke J, et al. Mature adipocytesinhibit in vitro differentiation of human preadipocytes via angiotensintype 1 receptors. Diabetes. (2002) 51:1699-707). Based on these findingsand recent evidence showing that lack of adipose tissue can promotediabetes by causing excess storage of fat in muscle, liver, and pancreas(Danforth E, Jr. Failure of adipocyte differentiation causes type IIdiabetes mellitus? Nat Genet. (2000) 26:13), Sharma and colleaguesproposed that blockade of the renin-angiotensin system per se mightprevent diabetes by promoting the recruitment and differentiation ofadipocytes (Sharma A M, et al. Angiotensin blockade prevents type 2diabetes by formation of fat cells. Hypertension. (2002) 40:609-11). Inthe current studies, we have found that moderate concentrations oftelmisartan and higher concentrations of irbesartan can activate PPARγwhich is known to promote adipogenesis, however, other ARBs failed toshow any effects on PPARγ gamma activity or adipogenesis. Thus, blockadeof angiotensin receptors per se is not sufficient to promote increasedPPARgamma activity or adipogenesis and not sufficient to prevent ortreat type 2 diabetes or any other insulin resistance syndrome includingthe metabolic syndrome.

In light of a number of clinical and experimental studies suggestingthat angiotensin converting enzyme (ACE) inhibitors can improve insulinsensitivity and decrease the incidence of new onset type 2 diabetes inpatients with hypertension, the question again arises as to whetherpharmacological interruption of the renin-angiotensin system by othermeans, such as with angiotensin receptor blockers (ARBs), could also bepredicted to be useful for preventing or treating type 2 diabetes orother insulin resistance syndromes (Yusuf S, et al. Ramipril and thedevelopment of diabetes. JAMA. 2001; 286:1882-5; Hansson L, et al.Effect of angiotensin-converting-enzyme inhibition compared withconventional therapy on cardiovascular morbidity and mortality inhypertension: the Captopril Prevention Project (CAPPP) randomized trial.Lancet. (1999) 353:611-6; Major outcomes in high-risk hypertensivepatients randomized to angiotensin-converting enzyme inhibitor orcalcium channel blocker vs diuretic: The Antihypertensive andLipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA.(2002) 288:2981-97; Bernobich E, et al. The role of the angiotensinsystem in cardiac glucose homeostasis: therapeutic implications. Drugs.(2002) 62:1295-314). However, recent studies have shown that the insulinsensitizing effects of ACE inhibitors are related to their effects onkinin metabolism rather than their effects on the renin-angiotensinsystem (Tomiyama H, et al. Kinins contribute to the improvement ofinsulin sensitivity during treatment with angiotensin converting enzymeinhibitor. Hypertension. (1994) 23:450-5; Shiuchi T, et al. ACEinhibitor improves insulin resistance in diabetic mouse via bradykininand NO. Hypertension. (2002) 40:329-34; Bernobich E, et al. The role ofthe angiotensin system in cardiac glucose homeostasis: therapeuticimplications. Drugs. (2002) 62:1295-314). Thus, based on the results ofstudies using ACE inhibitors, it could not have been predicted that anyof the existing ARBs would activate PPARγ and be useful for preventingor treating type 2 diabetes, the metabolic syndrome or any other insulinresistance syndrome.

SUMMARY OF THE INVENTION

While not wishing to be bound by theory, drugs that activate PPARgammacan cause fluid retention through a number of mechanisms. A surprisingfeature of this invention is that the fluid retention usually caused bydrugs that activate PPARgamma can be prevented or attenuated by blockadeof angiotensin II type 1 receptors. Because multiple mechanisms may beinvolved in the fluid retention caused by PPARgamma ligands, it couldnot have been predicted that blockade of angiotensin receptors couldprevent or attenuate the fluid retention caused by PPARgamma ligands inhumans. Thus, it could not have been predicted that ARBs that activatePPAR could be used to treat or prevent type 2 diabetes, the metabolicsyndrome, or other insulin resistance syndromes without increasing therisk for fluid retention, edema, or congestive heart failure.

Until the current discovery described herein, it was not known thatcertain ARBs could increase the activity of PPARgamma. Thus, it couldalso not have been predicted that certain ARBs could be used to treat orprevent insulin resistance syndromes, type 2 diabetes, the metabolicsyndrome or other conditions known to be treatable by drugs thatincrease the activity of PPARgamma.

The current discovery also provides improved methods for preventing andtreating inflammatory diseases without promoting or aggravating fluidretention, peripheral edema, pulmonary edema, or congestive heartfailure by administering PPAR activators that also antagonize theangiotensin II type 1 receptor. Although it has long been recognizedthat compounds that activate PPAR or block angiotensin II type 1receptors have anti-inflammatory effects, it could not have beenpredicted that certain compounds would have the capacity to bothactivate PPARs and block angiotensin receptors. Because such compoundsexert anti-inflammatory effects through multiple pathways (PPAR pathwayand the angiotensin receptor pathway), they provide a superior abilityto treat or prevent inflammatory diseases than PPAR activators or ARBsalone. Such compounds that activate PPARs and block angiotensinreceptors are also superior to PPAR activators because unlike currentlyrecognized PPAR activators, the compounds of the current invention donot promote or aggravate fluid retention, peripheral edema, pulmonaryedema or heart failure.

The current invention describes the surprising finding that drugs existand can be developed that block the angiotensin II Type 1 receptor(angiotensin receptor blockers or ARBs) and can also increase theactivity of PPARgamma. That is, some drugs exist that can function asboth an ARB and as a PPAR activator. Such agents include, but are notlimited to, telmisartan and irbesartan and can be used to prevent ortreat type 2 diabetes, the metabolic syndrome, insulin resistance, andother disorders responsive to PPARgamma activation includinginflammatory disorders without causing fluid retention, edema, orcongestive heart failure. Thus, angiotensin receptor blockers such astelmisartan and irbesartan can be surprisingly used to treat conditionsthat are known by those skilled in the art to be responsive to PPARgammaactivators and can do so without causing fluid retention, edema, orcongestive heart failure.

Because ARBs that increase the activity of PPARgamma do not causesubstantial fluid retention and do not increase the risk for edema andCHF, they represent a significant improvement over the currentlyrecognized drugs that increase the activity of PPARgamma. Specificexamples of ARBs that increase the activity of PPARgamma are providedtogether with a description of novel clinical uses of these agents andinstructions for such use. This invention also describes the fact thatnew ARBs can be developed that also increase the activity of PPARgammaor PPARgamma and PPARalpha. Such new ARBs will also be useful fortreating or preventing type 2 diabetes, the metabolic syndrome, andother disorders responsive to administration of drugs that activatePPARs without promoting fluid retention, peripheral edema, pulmonaryedema, or congestive heart failure.

Because the compounds of this invention also activate PPARs in additionto blocking the angiotensin II type 1 receptor, said compounds provide amore effective means of treating or preventing inflammatory andmetabolic disorders including atherosclerosis than compounds that blockthe angiotensin II type 1 receptor but do not activate PPARs.

Also surprisingly, by administering an ARB or ACE inhibitor prior to orconcurrently with compounds that activate PPARgamma either as separatepills or tablets or capsules, or by administering both drugs formulatedin a single pill or tablet or capsule, one can also prevent or treatglucose intolerance or type 2 diabetes and other PPAR responsivedisorders without causing fluid retention, edema, or congestive heartfailure.

This invention relates to methods for treating or prophylacticallypreventing an inflammatory or metabolic disorder in a mammal (human ornon-human) without causing, promoting, or aggravating fluid retention,peripheral edema, pulmonary edema, or congestive heart failure, byadministering to a mammal in need thereof, a therapeutically effectiveamount of a compound sufficient to partially or fully activateperoxisome proliferator activated receptors (PPARs) and partially orfully inhibit, antagonize or block the activity of angiotensin II type 1receptors.

In one embodiment the mammal is a human child, adolescent or adult andthe therapeutically effective amount of the compound is used to preparea medicament for treatment of the metabolic disorder in the human.

In one embodiment, said compound increases the activity of the PPARsubtype, PPARgamma or the PPARgamma-retinoid X receptor (PPARgamma-RXR)heterodimer, independently or in combination with an increase inactivity of PPARalpha, PPARdelta, or both PPARalpha and PPARdelta.

In one embodiment said compound is administered in a pharmacologicallyacceptable form and in a therapeutically effective amount sufficient toprophylactically prevent, slow, delay or treat a metabolic disorder ordisease selected from the group consisting of insulin resistance,glucose intolerance, impaired glucose tolerance, impaired fasting serumglucose, impaired fasting blood glucose, hyperinsulinemia, pre-diabetes,type 1 diabetes, type 2 diabetes mellitus, insulin-resistanthypertension, the metabolic syndrome, the metabolic hypertensivesyndrome, (metabolic) syndrome X, the dysmetabolic syndrome, obesity,visceral obesity, hypertriglyceridemia, elevated serum concentrations offree fatty acids, elevated serum concentrations of C-reactive protein,elevated serum concentrations of lipoprotein(a), elevated serumconcentrations of homocysteine, elevated serum concentrations of small,dense low-density lipoprotein (LDL)-cholesterol, elevated serumconcentrations of lipoprotein-associated phospholipase (A2), reducedserum concentrations of high density lipoprotein (HDL)-cholesterol,reduced serum concentrations of HDL(2b)-cholesterol, and reduced serumconcentrations of adiponectin.

In a particular embodiment, as described in U.S. Pat. No. 6,100,252(Heterocyclic compounds and their use as angiotensin antagonists byNaka, et al.) the compound is of the general formula:

[wherein R1 is an optionally substituted hydrocarbon residue which isoptionally bonded through a hetero-atom; R2 is an optionally substituted5-7 membered heterocyclic residue having, as a group capable ofconstituting the ring, a carbonyl group, a thiocarbonyl group, anoptionally oxidized sulfur atom or a group convertible into them; X is adirect bond or a spacer having an atomic length of two or less betweenthe ring Y and the ring W; W and Y are independently an optionallysubstituted aromatic-hydrocarbon residue optionally containing ahetero-atom or an optionally substituted heterocyclic residue; n is aninteger of 1 or 2; a and b forming the heterocyclic residue areindependently one or two optionally substituted carbon or hetero atoms;c is an optionally substituted carbon or hetero atom; and, in the groupof the formula:

substituents on adjacent two atoms forming the ring are optionallybonded to each other to form a 5-6 membered ring together with the twoatoms forming the ring] or a pharmaceutically acceptable salt thereof,or a pharmaceutically acceptable solvate thereof.

In one embodiment, the compound is formulated for oral administration.In another embodiment, the compound is formulated for topicaladministration.

In a preferred embodiment, the compound is telmisartan, or an analogthereof. In another preferred embodiment, the compound is irbesartan, oran analog thereof In some embodiments, the total effective daily orallyadministered dose is selected from the range of from about 20 mg to 1000mg.

The present invention further provides methods for screening compoundsfor treating or prophylactically preventing an inflammatory or metabolicdisorder in a mammal by selecting a compound having the properties of:(a) at least partially activating peroxisome proliferator activatedreceptors (PPARs); and (b) at least partially inhibiting, antagonizingor blocking an activity of angiotensin II type 1 receptors. In someembodiments the method furthet includes selecting a compound that doesnot cause, promote, or aggravate fluid retention, peripheral edema,pulmonary edema, or congestive heart failure in the mammal.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a method for preventing, delaying or treatinginsulin resistance, pre-diabetes, glucose intolerance, impaired glucosetolerance, the metabolic syndrome, type 2 diabetes, or other insulinresistance syndromes without causing systemic fluid retention, orincreasing the risk for fluid retention, peripheral edema, pulmonaryedema, or congestive heart failure by administering a compound thatincreases both the activity of peroxisome proliferator activatedreceptors and blocks/antagonizes activity of the angiotensin II type 1receptor. This invention further relates to novel clinical uses ofcertain angiotensin II type 1 receptor blockers (ARBs) based on thediscovery that said compounds can increase the activity of peroxisomeproliferator activated receptors (PPARs), PPARγ, PPARα, or PPARδ, or anycombination thereof, and can be used to treat and to preventPPAR-regulated diseases and their complications including metabolic,inflammatory, proliferative, and cardiovascular diseases not previouslyrecognized to be therapeutic targets for ARBs or more effectively thanARBs that do not activate PPARs. This invention further relates tomethods for developing and using drugs that have the dual ability toblock or inhibit activity of the renin-angiotensin-aldosterone systemand to activate PPARs. Another aspect of this invention relates tomethods for screening libraries of compounds to determine which arelikely candidates for use in the practice of this invention.

Definitions

Body mass index (BMI) of a human patient is defined as the weight inkilograms divided by the square of the height in meters, such that BMIhas units of kg/m².

Overweight is defined as the condition wherein the individual has a BMIgreater than or 25 kg/m² and less than 30 kg/m².

Obesity is defined as the condition wherein the individual has a BMIequal to or greater than 30 kg/m². In another aspect, the term obesityis used to mean visceral obesity.

Visceral obesity is defined as a waist-to-hip ration of 1.0 in men and0.8 in women, which, in another aspect defines the risk for insulinresistance and the development of pre-diabetes.

Euglycemia is defined as the condition in which a subject has a fastingblood glucose concentration within the normal range, greater than 70mg/dl (3.89 mmol/L) and less than 110 mg/dl (6.11 mmol/L). The wordfasting has the usual meaning as a medical term.

Impaired glucose tolerance (IGT), is defined as the condition in which asubject has a fasting blood glucose concentration or fasting serumglucose concentration greater than 110 mg/dl and less than 126 mg/dl(7.00 mmol/L), or a 2 hour postprandial blood glucose or serum glucoseconcentration greater than 140 mg/dl (7.78 mmol/L) and less than 200mg/dl (11.11 mmol/L). The term impaired glucose tolerance is alsointended to apply to the condition of impaired fasting glucose.

Hyperinsulinemia is defined as the condition in which a subject withinsulin resistance, with or without euglycemia, in which the fasting orpostprandial serum or plasma insulin concentration is elevated abovethat of normal, lean individuals without insulin resistance, having awaist-to-hip ration <1.0 (for men) or <0.8 (for women).

The terms “insulin-sensitizing”, “insulin resistance-improving” or“insulin resistance-lowering” are synonymous and used interchangeably.

Insulin resistance is defined as a state in which circulating insulinlevels in excess of the normal response to a glucose load are requiredto maintain the euglycemic state (Ford E S, et al. JAMA. (2002)287:356-9). Insulin resistance, and the response of a patient withinsulin resistance to therapy, may be quantified by assessing thehomeostasis model assessment to insulin resistance (HOMA-IR) score, areliable indicator of insulin resistance (Katsuki A, et al. DiabetesCare 2001; 24:362-5). The estimate of insulin resistance by thehomeostasis assessment model (HOMA)-IR score is calculated with theformula (Galvin P, et al. Diabet Med 1992; 9:921-8):

HOMA-IR=[fasting serum insulin (μU/mL)]×[fasting plasma glucose(mmol/L)/22.5]

Patients with a predisposition for the development of IGT or type 2diabetes are those having euglycemia with hyperinsulinemia and are bydefinition, insulin resistant. A typical patient with insulin resistanceis usually overweight or obese.

The term pre-diabetes is the condition wherein an individual ispre-disposed to the development of type 2 diabetes. Pre-diabetes extendsthe definition of impaired glucose tolerance to include individuals witha fasting blood glucose within the high normal range >100 mg/dL (J. B.Meigs, et al. Diabetes 2003; 52:1475-1484) and fasting hyperinsulinemia(elevated plasma insulin concentration). The scientific and medicalbasis for identifying pre-diabetes as a serious health threat is laidout in a Position Statement entitled “The Prevention or Delay of Type 2Diabetes” issued jointly by the American Diabetes Association and theNational Institute of Diabetes and Digestive and Kidney Diseases(Diabetes Care 2002; 25:742-749).

Individuals likely to have insulin resistance are those who have two ormore of the following attributes: 1) overweight or obese, 2) high bloodpressure, 3) hyperlipidemia, 4) one or more 1^(st) degree relative witha diagnosis of IGT or type 2 diabetes. Insulin resistance can beconfirmed in these individuals by calculating HOMA-IR score. For thepurpose of this invention, insulin resistance is defined as the clinicalcondition in which an individual has a HOMA-IR score >4.0 or a HOMA-IRscore above the upper limit of normal as defined for the laboratoryperforming the glucose and insulin assays.

Type 2 diabetes is defined as the condition in which a subject has afasting blood glucose or serum glucose concentration greater than 125mg/dl (6.94 mmol/L).

The metabolic syndrome, also called syndrome X (when used in the contextof a metabolic disorder), also called the dysmetabolic syndrome is asyndrome complex with the cardinal feature being insulin resistance(Laaksonen D E, et al. Am J Epidemiol 2002; 156:1070-7). According tothe ATP III/NCEP guidelines (Executive Summary of the Third Report ofthe National Cholesterol Education Program (NCEP) Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel III) JAMA: Journal of the American MedicalAssociation (2001) 285:2486-2497), diagnosis of the metabolic syndromeis made when three or more of the following risk factors are present:

-   -   1. Abdominal obesity, defined as waist circumference >40 inches        or 102 cm in men, and >35 inches or 94 cm in women    -   2. Triglycerides: ≧150 mg/dL    -   3. HDL-cholesterol <40 mg/dL in men    -   4. Blood pressure ≧130/85 mm Hg (SBP≧130 or DBP≧85)    -   5. Fasting blood glucose ≧110 mg/dL

The NCEP definitions have been validated (Laaksonen D E, et al. Am JEpidemiol. (2002) 156:1070-7).

The term congestive heart failure (CHF) includes heart failure of anyetiology, including but not limited to, heart failure with diastolicdysfunction, heart failure with systolic dysfunction, heart failureassociated with cardiac hypertrophy, and heart failure that develops asa result of infectious myocarditis, inflammatory myocarditis, chemicalmyocarditis, cardiomyopathy of any etiology, hypertrophiccardiomyopathy, congenital cardiomyopathy, and cardiomyopathy associatedwith ischemic heart disease or myocardial infarction.

The term PPAR means one or any combination of PPARalpha, PPARgamma andPPARdelta.

The term PPARgamma means one or any combination of PPARgamma1,PPARgamma2, PPARgamma3.

The terms PPAR activator or PPARgamma activator means any compound that,by any mechanism, increases, or causes an increase in the activity ofPPARgamma or the heterodimer of PPARgamma with the retinoid X receptor(RXR), either by direct binding to either PPARgamma or RXR or indirectlythrough any other mechanism that affects the ability of PPARgamma or thePPARgamma-RXR heterodimer to influence gene expression. Such PPARactivators may affect PPARgamma activity either alone or in combinationwith activation of other PPARs including either PPARalpha, PPARdelta, orboth PPARalpha and PPAR delta.

A PPAR-dependent disease is a disease in which 1) administration of aPPAR ligand slows, ameliorates, stops or reverses the pathologicalprocess, and or 2) said disease is associated with impaired signaltransduction upstream from PPAR and its interaction with the genetranscription machinery, and or 3) activation, partial activation orantagonism by a PPAR ligand (PPARα, PPARγ, PPARδ) leads to theprevention, amelioration, cure, or arrest of said disease orpathological process.

An angiotensin II-dependent disease is a disease in which: 1)administration of a AT1 receptor antagonist slows, ameliorates, stops orreverses the pathological process, and or 2) said disease is associatedwith impaired signal transduction within the RAAS system, and or 3) saiddisease is facilitated or exacerbated by activation of the AT1 receptorby angiotensin II, the initiating step being the by binding ofangiotensin II the AT1 receptor. Because angiotensin II is apro-inflammatory mediator, angiotensin II-dependent diseases areexpected to be inflammatory in nature (Phillips M I, Kagiyama S. CurrOpin Investig Drugs 2002; 3:569-77). ARBs have the potential toameliorate inflammatory diseases, and because PPAR ligands also functionas anti-inflammatory agents with differing mechanisms of action, dualARB/PPAR ligands would have novel, more potent, synergistic effects oninflammatory diseases (Tham D M, et al. Physiol Genomics 2002;11:21-30).

An inflammatory disease is a disease associated dysfunction of theimmune system, exemplified as, but not limited to: 1) increasedproduction of inflammatory cytokines (interleukin(IL)-1beta, IL-2, IL-6,IL-8, IL-12, tumor necrosis factor-α, interferon-γ, monocytechemoattractant protein-1), 2) increased conversion of Th2 lymphocytesto the Th1 phenotype or increased Th1/Th2 ratio, 3) inappropriatefunction of NK (killer) T lymphocytes resulting in auto-antibodies andlack of “self” recognition resulting in an autoimmune disease, 4)increased expression or activation of inflammatory nuclear transcriptionfactors (NFAT, NF-κB, AP-1, JNK/STAT), 5) increased expression of iNOS.

A proliferative disease is a disease associated with: 1) pathologicalproliferation of normally quiescent cells, 2) pathological migration ofcells from their normal location (e.g. metastasis of neoplastic cells),3) pathological expression of proteolytic enzymes such as the matrixmetalloproteinases (collagenases, gelatinases, elastases), 4)pathological angiogenesis as in proliferative retinopathy and tumormetastasis.

Angiogenesis is the process by which normally quiescent endotheliumresponds to physiological or pathological stimuli (such as proliferatingendometrium, injury, tumor growth, or diabetic retinopathy) resulting inpathological proliferation of blood vessels (neovascularization).Pathological angiogenesis (neovascularization) is an unregulated,unbridled process resulting as in inappropriate vascular proliferationas in tumor neovascularization, lymphangiogenesis, and tumor metastasis.

A degenerative disease is a disease associated with deterioration ordestruction normal tissue, resulting from immune dysregulation resultingin the upregulation of one or more inflammatory nuclear transcriptionfactors, inflammatory cytokines and other inflammatory molecules such asproteases (e.g. MMP-9) and iNOS, leading to pathological degeneration ofthe respective cell or tissue or organ which is the therapeutic target.

The term heart failure includes congestive heart failure, heart failurewith diastolic dysfunction, heart failure with systolic dysfunction,heart failure associated with cardiac hypertrophy, and heart failurethat develops as a result of chemically induced cardiomyopathy,congenital cardiomyopathy, and cardiomyopathy associated with ischemicheart disease or myocardial infarction.

The current invention relates to the surprising discovery that certainARBs can also function as PPARgamma activators and can be used toprevent, delay, slow, arrest or treat insulin resistance, pre-diabetes,glucose intolerance, impaired glucose tolerance, the metabolic syndrome,type 2 diabetes, or other insulin resistance syndromes, as well as otherdisorders responsive to PPAR activators without increasing the risk forfluid retention, peripheral edema, pulmonary edema, or congestive heartfailure. Thus, the current invention provides novel uses for certainARBs for the treatment or prevention of diseases known to be responsiveto drugs that increase PPARgamma activity including metabolic,endocrine, proliferative, autoimmune, immunomodulatory and inflammatorydiseases and certain infective diseases. Accordingly, the presentinvention includes the discovery of how to make, identify, and use drugsthat activate PPARgamma and that do not increase the risk of fluidretention, edema, or congestive heart failure like existing drugs thatactivate PPARgamma. This invention describes the discovery that it ispossible to make and use compounds that have the dual ability to blockor inhibit the renin-angiotensin-aldosterone system and the ability toactivate PPARgamma. The invention provides specific examples of suchcompounds not previously recognized to have this dual ability and showsthat these compounds can be used to treat conditions not previouslyknown to be responsive to such compounds. Thus, this invention includesthe surprising discovery that one can use certain to treat disordersresponsive to treatment with PPAR activators.

The present invention provides novel uses for ARBs that also activatePPARs for the treatment or prevention of diseases known to be responsiveto PPAR ligands, in particular PPARgamma partial agonists or PPARgammafull agonists. Target diseases include metabolic, endocrine,proliferative, degenerative, autoimmune, atopic, and inflammatorydiseases. The present invention also relates to the identification ofnovel or previously unknown ARBs that also activate PPARgamma and have areduced propensity for causing fluid retention, edema, or congestiveheart failure compared to other activators of PPARgamma. Thus, thepresent invention includes the discovery of how to identify compoundsthat block the rennin-angiotensin system and, at the same time, activatePPARgamma but have a significantly lower risk of causing fluidretention, edema, or congestive heart failure. The invention providesspecific examples of ARBs not previously recognized to have this dualability and reveals why these compounds can be used to treat conditionsnot previously known to be responsive to said compounds. Thus, thisinvention includes the surprising discovery that one can use certainARBs for the purpose of treating or preventing disorders responsive totreatment with PPAR ligands, said ligands having improved safety andtherapeutic efficacy.

This invention relates to the unpredictable and surprising discoverythat certain compounds can block the rennin-angiotensin system byantagonizing the AT1 receptor while activating PPARs, in particular,PPARgamma.

In another aspect this invention relates to novel clinical uses of ARBsin the prevention and treatment of PPAR-responsive conditions ordiseases.

In another aspect this invention relates to novel clinical uses of ARBsin the prevention and treatment of PPAR-related conditions or diseasesmediated through PPAR-dependent regulation of or interaction withrelated nuclear receptors, including the retinoid X receptor (RXR),retinoid orphan-related receptor (ROR), liver X receptor (LXR),farnesoid X receptor (FXR), vitamin D receptor (VDR), estrogen receptors(ER-alpha and ER-beta), glucocorticoid receptor (GR), thyroid receptor(TR) and androgen receptor (AR).

In another aspect this invention relates to design and identification ofthose ARBs that modulate the activity of PPARs, thus providing for saferand enhanced therapeutic efficacy for preventing or treatingPPAR-mediated conditions or diseases, or the end-organ complications ofthese diseases.

In another aspect, this invention relates to the identification of lowtoxicity PPAR ligands that are effective ARBs or ACE inhibitors byscreening with AT1 receptor binding assays.

In another aspect, this invention relates to methods for identifyingARBs or derivatives thereof, that can be made to further enhance theirability to activate PPAR and to more effectively treat PPAR-responsiveor PPAR-mediated diseases, disorders or conditions.

Compounds according to the present invention have renoprotective effectsand are more effective for treating renal diseases or limiting the rateof progression of renal diseases (e.g. glomerular nephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,polycystic kidney diseases, and diabetic nephropathy) compared tocompounds that do not have this dual ability to inhibit the activity ofthe renin angiotensin aldosterone system and to activate PPARs.

This invention identifies ARBs that can be used as monotherapy, or incombination with one or more other pharmacological agents, or asadjunctive therapy to prevent, delay, slow, arrest or treat:

1. Metabolic diseases associated with insulin resistance such asimpaired glucose tolerance, glucose intolerance, pre-diabetes, themetabolic syndrome (also termed metabolic syndrome X or the dysmetabolicsyndrome), obesity, type 2 diabetes mellitus, gestational diabetes,polycystic ovarian syndrome, Werner's syndrome;

2. Dyslipidemias associated with hyperlipemia, elevated free fattyacids, hypercholesterolemia, hypertriglyceridemia, elevated low densitylipoprotein-(LDL)-cholesterol, elevated very low densitylipoprotein-(VLDL)-cholesterol, elevated intermediate densitylipoprotein-(IDL)-cholesterol, or reduced high densitylipoprotein-(HDL)-cholesterol;

3. Inflammatory skin diseases such as psoriasis, atopic dermatitis,seborrheic dermatitis, solar dermatitis;

4. Inflammatory or proliferative diseases such as atherosclerosis,atherogenesis, vascular stenosis or restenosis, rheumatoid arthritis,ulcerative colitis, Crohn's disease, endometriosis;Inflammatory,neurodegenerative or neuropsychiatric diseases such as Alzheimer'sdisease, Parkinson's disease, multiple sclerosis, depression,psychoses;Benign, malignant tumor or metastatic tumor growth;

5. Neovascularization and pathological angiogenesis associated withneoplasia, tumor growth and metastasis;

6. Inflammatory or proliferative ocular diseases including cornealangiogenesis, chorio-retinal retinopathy, age-related maculardegeneration and neovascularization, uveitis, glaucoma, iritis,keratitis, retinitis;

7. Pro-thrombotic diseases as in hypercoagulable or thrombotic states,such as diseases associated with elevated plasminogen activatorinhibitor-1 (PAH), thombotic or thromboembolic diseases, atheromaformation;

8. Autoimmune diseases such as type 1 diabetes mellitus, multiplesclerosis, Parkinson's disease, amyotropic lateral sclerosis;

9. Allograft rejection upon or subsequent to transplantation, andcomplications associated with both acute and chronic allograftrejection;

10. Infective diseases caused by DNA viruses, RNA viruses andretroviruses, including AIDS, SARS and hepatitis C;

11. Infective diseases caused by prions, such as kuru, Cretzfeld-Jackobdisease and spongiform encephalopathies;

12. Complications associated with viral and prion-related infections,including CNS-related complications and CNS-related degenerativeconditions that result in encephalopathy, dementia and cachexia;

13. Cachexia associated with chronic diseases such as CHF, cancer,multiple sclerosis, chronic infections, anorexia nervosa, bullemia;

14. CD-36 mediated diseases such as certain metabolic diseases,retinitis pigmentosa and malaria 15. Conditions such as obesity,including methods for controlling appetite or food intake, diet andanorexia.

A compound or a pharmaceutical composition according to the presentinvention is a PPARgamma activator which has less toxicity than otherPPAR activators of the current art. Less toxicity principally refers tosubstantially reduced potential for fluid retention, edema or heartfailure. Said compound or pharmaceutical composition according to thepresent invention may also be used prevent, delay, slow, arrest or treatchronic medical pathologies and diseases, including: a) diabeticcomplications and diabetes-associated conditions includingsteatohepatitis, neuropathy, nephropathy, retinopathy,chorioretinopathy, choroidal neovascularization, retinalneovcascularization, macular degeneration, retinal detachment, glaucoma,cataract, microangiopathy, atherosclerosis, ischemic heart disease,ischemic cerebrovascular disease, stroke, peripheral arteriosclerosis,cerebral arteriosclerosis, coronary arteriosclerosis,hyperinsulinemia-induced sensory disorder, obesity, heart failure,myocardial infarction, angina pectoris, cerebral infarction, chroniccardiomyopathy, cardiac fibrosis, renal disorders, glomerular nephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,terminal renal disorders, microangiopathy, atherosclerosis, ischemicheart disease, ischemic cerebrovascular disease, diabetic cachexia, andthe like; b) cachexia resulting from chronic diseases or conditionsincluding carcinomatous cachexia, hemophathic cachexia, endocrinopathiccachexia, infectious cachexia, cachexia induced by acquiredimmunodeficiency syndrome, cachexia associated with congestive heartfailure or chronic cardiomyopathy, anorexia nervosa, and the like; c)degenerative diseases including osteopenia, osteoporosis, musculardystrophy, rheumatoid arthritis, spondylitis deformans, osteoarthritis,lumbago, gout, neuralgia, gastritis, hepatitis, pneumonia, pancreatitisand the like. In addition, a compound according to the invention mayalso be employed as a pharmaceutical for controlling appetite or foodintake, diet and anorexia.

A compound or a pharmaceutical composition according to the presentinvention has a blood sugar reducing effect, a blood lipid reducingeffect, a blood insulin reducing effect, an insulin sensitivityenhancing effect, an insulin resistance improving effect, a body weightreducing effect, a central body girth (measured as waist:hip ratio)reducing effect, a body fat mass reducing effect, through effects onPPARgamma activity, PPARgamma-RXR, or through effects on relater nuclearreceptors, including FXR, LXR, ROR, cAMP-response element-bindingprotein (CREB), CREB-binding protein (CBP), CBP/p300, sterol regulatorybinding proteins (SREBPs), steroid receptor coactivator-1 (SRC-1),PPARgamma coactivator-1alpha (PGC-1 alpha), PPARgamma coactivator-1beta(PGC-1 beta) and PPAR-binding protein (PBP).

While the dose of a compound or a pharmaceutical composition accordingto the present invention varies depending on various factors such as thesubject to be treated, the administration route, the disease or thecondition to be treated, a compound according to the present inventionas an active ingredient may for example be given orally to an human at adaily dose of about 0.05 to 100 mg/kg body weight, preferably about 0.1to 10 mg/kg body weight, preferably one to three times a day, with asingle dose providing therapeutic efficacy for at least 24 hr beingpreferred. It is also contemplated that the therapies described in thepresent invention is applicable to children and adults.

A compound according to the present invention has a blood sugar reducingeffect, a blood lipid reducing effect, a blood insulin reducing effect,an insulin sensitivity enhancing effect, an insulin resistance improvingeffect, a body weight reducing effect, a central body girth (measured aswaist:hip ratio) reducing effect, a body fat mass reducing effect,through ligand-dependent PPAR activity or PPAR-related nuclear receptorfunction activities. A PPAR is a nuclear transcription factor, and theterm is used here to encompass PPARγ, PPARα, PPARδ nuclear receptorsthat function as DNA-binding transcription factors having as a secondarymodulating ligand for a dimeric nuclear receptor partner, such as anoil-soluble vitamin (vitamin A, vitamin D), a retinoid, or steroidhormone, and may be any of a monomer receptor, a homodimer receptor anda heterodimer receptor. A monomer receptor is exemplified by retinoid Oreceptor (hereinafter abbreviated occasionally as RORα (GenBankAccession No. L14611) RORβ (GenBank Accession No. L14160), RORγ (GenBankAccession No. U16997); Rev-erbα. (GenBank Accession No. M24898),Rev-erbβ. (GenBank Accession No. L31785); ERRα. (GenBank Accession No.X51416), ERRβ (GenBank Accession No. X51417); Ftz-FIα. (GenBankAccession No. S65876), Ftz-FIβ. (GenBank Accession No. M81385);TIx(GenBank Accession No. S77482); GCNF (GenBank Accession No. U14666) andthe like. A homodimer receptor may for example be a homodimer formedfrom retinoid X receptor (hereinafter abbreviated occasionally as RXRα(GenBank Accession No. X52773), RXRβ. (GenBank Accession No. M84820),RXRγ. (GenBank Accession No. U38480); COUPα (GenBank Accession No.X12795), COUPβ (GenBank Accession No. M64497), COUPγ (GenBank AccessionNo. X12794);TR2α (GenBank Accession No. M29960), TR2β (GenBank AccessionNo. L27586); or, HNF4α (GenBank Accession No. X76930), 1-INF4.γ.(GenBank Accession No. Z49826) and the like. A heterodimer receptor mayfor example be a heterodimer formed from retinoid receptor X (RXRα, RXRβor RXRγ) described above together with one receptor selected from thegroup consisting of retinoid A receptor (hereinafter abbreviatedoccasionally as RARα (GenBank Accession No. X06614), RARβ (GenBankAccession No. Y00291), RARγ (GenBank Accession No. M24857); a thyroidalhormone receptor (hereinafter abbreviated occasionally as TRα (GenBankAccession No. M24748), TRβ (GenBank Accession No. M26747); a vitamin Dreceptor (VDR) (GenBank Accession No. J03258); a peroxisomeproliferator-activated receptor (hereinafter abbreviated occasionally asPPARα (GenBank Accession No. L02932), PPARβ (PPARdelta) (GenBankAccession No. U10375), PPARγ (GenBank Accession No. L40904); LXRα(GenBank Accession No. U22662), LXRβ (GenBank Accession No. U14534); FXR(GenBank Accession No. U18374); MB67 (GenBank Accession No. L29263); ONR(GenBank Accession No. X75163;and NUR.α. (GenBank Accession No. L13740),NUR.β. (GenBank Accession No. X75918), NUR.γ. (GenBank Accession No.U12767).

The current invention constitutes the surprising finding that certainARBs can activate PPARγ, promote adipogenesis, lower (improve) insulinresistance, and can be used to treat or prevent the metabolic syndromeand components thereof (see definitions) and type 2 diabetes. Among theARBs presently approved for human use telmisartan and irbesartan arespecific examples of compounds of this invention, and can surprisinglybe used to treat or prevent insulin resistance, the metabolic syndromeand type 2 diabetes (i.e. lower hyperinsulinemia and/or hyperglycemia),lower triglycerides, and elevate HDL-cholesterol. An extension of thisinvention is the predictive design of derivatives of existing ARBs toimprove their insulin resistance-lowering activity by increasing theEC50 for activation of PPARγ.

It has been previously shown that the risk for diabetes in patientsgiven ARBs is lower than that in patients given other antihypertensivedrugs. However, until the current discovery described herein, it was notknown that these drugs could activate PPARγ and it could not have beenpredicted that these drugs could be used to treat insulin resistancesyndromes such as type 2 diabetes or other conditions known to betreatable by PPAR ligands. For example, the lower risk of diabetesreported in patients given ARBs versus β-blockers (Dahlof B, et al.Lancet 2002; 359:995-1003) could have been due to the fact thatβ-blockers aggravate insulin resistance and therefore, the results ofclinical studies comparing ARBs to other agents cannot be used topredict whether ARBs can be used to treat diabetes or other disordersresponsive to PPARγ ligands.

Because ARBs do not cause substantial fluid retention and do notincrease the risk for edema and heart failure, they represent asignificant improvement over the currently recognized PPAR ligands.Specific examples of ARBs that activate PPARγ are provided together witha description of novel clinical uses of these agents and instructionsfor such use. This invention also describes the novel finding that onecan derive new ARBs with greater ability to activate PPARs than existingARBs and that such ARBs with enhanced ability to activate PPARs can beused to prevent or treat clinical disorders known to be responsive toPPAR ligands without causing the degree or extent of side effects offluid retention, edema, or congestive heart failure caused by currentlymarketed PPAR ligands. Surprisingly, one can also make modifications tocurrently available ARBs that will significantly enhance their abilityto activate PPARs and therefore enhance their ability to treat disordersknown to be responsive to PPAR ligands. Such compounds also represent animprovement over existing ARBs as they have greater ability to activatePPARs and therefore have the added benefits of improving clinicaldisorders that are responsive to treatment with PPAR activators. Usingthe methods of this invention, one can identify, develop, and use PPARligands that have the ability to inhibit ACE activity or blockangiotensin receptors. Such compounds represent a novel approach totreating disorders known to be responsive to PPAR ligands because theydo not promote fluid retention, edema, or congestive heart failure tothe extent that currently available PPAR ligands are know to do.

Specific examples of ARBs that activate PPARγ are provided together witha description of novel clinical uses of these agents and instructionsfor such use. This invention also describes the novel finding that onecan derive new ARBs with greater ability to activate PPARs than existingARBs and that such ARBs, having enhanced ability to activate PPARs, canbe used to prevent or treat clinical disorders known to be responsive toPPAR ligands without causing the degree or extent of side effects offluid retention, edema, or congestive heart failure as do currentlymarketed PPARγ ligands. Surprisingly, one can structurally modifycurrently available ARBs to significantly enhance their ability toactivate PPARs and therefore enhance their ability to treat disordersknown to be responsive to PPAR ligands. Such compounds also represent animprovement over existing ARBs in that they more effectively activatePPARs and therefore have the added benefits of improving clinicaldisorders that are responsive to treatment with PPAR activators. Usingthe methods of this invention, one can identify, develop, and use PPARligands that have the ability to antagonize the AT1 receptor. Suchcompounds represent a novel approach to treating disorders known to beresponsive to PPAR ligands because they do not promote fluid retention,edema, or congestive heart failure to the extent that currentlyavailable PPAR ligands are know to do. While not wishing to be bound bytheory, PPARγ ligands cause fluid retention through a number ofmechanisms. A surprising feature of this invention is that the fluidretention usually caused by PPARγ ligands can be prevented or attenuatedby blockade of AT1 receptors. Because blockade of the AT1 receptor doesnot always attenuate or prevent fluid retention in some animal modelstreated with PPARγ ligands, and because multiple mechanisms may beinvolved in the fluid retention caused by PPARγ ligands, it could nothave been predicted that blockade of AT1 receptors could prevent orattenuate the fluid retention caused by PPARγ ligands in humans. Alsosurprisingly, by administering an ARB prior to or concurrently withcompounds that activate PPARgamma either as separate pills or tablets,or by administering both drugs formulated in a single pill or tablet,one can also treat glucose intolerance or type 2 diabetes and other PPARresponsive disorders without causing fluid retention, edema, orcongestive heart failure.

Because PPARγ is not recognized to be structurally related to the AT1receptor, ARBs would not be expected to activate PPARγ. Thus, it couldnot have been predicted that one could use any existing ARB to activatePPARγ. Therefore, one could not have predicted that ARBs would be usefulto treat disorders responsive to PPARγ ligands or that one could designdrugs that have the ability to block the AT1 receptor while also havingthe ability to activate PPARγ. This invention describes the surprisingdiscovery that compounds can be designed to antagonize the AT1 receptorwhile also possessing the ability to activate PPARγ, and that suchcompounds can be surprisingly useful for treating conditions known to beresponsive to PPARγ ligands without promoting fluid retention, edema, orheart failure. Also surprisingly, by administering an ARB that alsoactivates PPARγ, one can also treat insulin resistance, the metabolicsyndrome, glucose intolerance, type 2 diabetes, polycystic ovariansyndrome, as well as other PPARγ-responsive disorders without causingfluid retention, edema, or congestive heart failure. These findingssuggested that like the anti-diabetic thiazolidinedione PPARγ agonists,telmisartan may also improve insulin resistance. We determined thatadministration of telmisartan to a patient with the metabolic syndromeimproved insulin resistance as determined by reduction of the HOMA-IRscore (see definitions). When administered to a patient with type 2diabetes, telmisartan lowered the hyperglycemia, lowers plasmatriglycerides, and elevated blood HDL-cholesterol. These finding led tothe surprising discovery, and invention, that ARBs that also activatePPARγ are useful for preventing and treating the metabolic syndrome,type 2 diabetes, and improving lipid metabolism by loweringtriglycerides and elevating HDL-cholesterol. These insulin-sensitizing,antidiabetic effects are limited to certain ARBs, such as telmisartanand irbesartan. ARBs such as valsartan and eprosartan which do notactivate PPARγ at doses reasonably achievable at therapeutic doses, didnot promote adipogenesis, a property of telmisartan and theinsulin-sensitizing thiazolidinedione PPARγ agonists. Thus, the propertyof reducing insulin resistance is restricted within the class ofnon-peptide ARBs known as “sartans”, and are unpredictable surprisingand non-obvious. This invention discloses methods of determining which“sartans” or other AT1 receptor antagonists may function as aninsulin-sensitizing, insulin resistance-improving or anti-diabeticagent.

Insulin resistant states predispose to inflammatory, proliferative anddegenerative diseases such as atherosclerosis, atherogenesis, vascularstenosis or restenosis after invasive intravascular procedures,cardiomyopathy, and myocardial fibrosis. Moreover, the excessive use ofglucocorticoids and/or immunosuppressive agents, as in the treatment ofchronic inflammatory diseases and complications of immunosuppression inallograft rejection, such as osteoporosis, Cushing's disease,lipodystrophy, insulin resistance, type 2 diabetes, hyperlipidemia,transplantation-related hypertension, atherosclerosis, renal disease,arteritis and endarteritis. This invention predicts that administrationof an ARB that also activates PPARγ would result in the clinicalimprovement of these conditions.

Uses of the Invention

The methods of treatment provided by this invention are practiced byadministering to a human or vertebrate animal in need a dose of acompound, or a pharmaceutically acceptable salt, ester, solvate ortautomer thereof, that blocks or antagonizes the angiotensin II type 1receptor and activates either PPARgamma alone or in combination withPPARalpha, or PPARdelta both PPARalpha and PPAR gamma. In anotheraspect, the novel compounds used to practice this invention are setforth above. The specific diseases and associated disorders that can betreated with the compounds described in this invention are listed inTables I through X.

TABLE I Examples of dermatological disorders and inflammatory skindisorders treatable using compounds of this invention Kertinizing skindiseases, keratitis, hidradenitis, ichthyosis, melasma Psoriasis (allforms, including p. vulgaris, p. guttata, p. discoidea, p. anthropica,p. universalis) Acne (all forms, including a. vulgaris, a. rosacea, a.inversa, cystic acne) Warts, verruca (all forms, including common warts,anogenital (venereal) warts, viral warts including human papilloma virus(HPV) infections, conjunctival warts, oral/buccal warts) Acute andchronic dermatitides (inflammation of the skin), atopic dermatitis,allergic dermatitis, contact dermatitis, cosmetic dermatitis, chemicaldermatitis, seborrheic dermatitis, solar dermatitis, acute and chroniceczema, diaper rash, sunburn Lupus associated skin lesions Keratosessuch as seborrheic keratosis, senile keratosis, actinic keratosis,photo-induced keratosis, skin aging, thinning skin, dry skin, wrinkleformation, photo-induced skin aging, keratosis follicularis Keloids andprophylaxis against keloid formation Leukoplakia, lichen planusUrticaria, pruritus Androgenic alopecia in men and women, hirsutism inwomen

TABLE II Examples of psychiatric disorders treatable using compoundsdescribed in this invention Depression, primary depression or depressionsecondary to chronic diseases and medications Dysphoric mood disordersObsessive compulsive disorder Dysthymic disorders Manic depressive(unipolar or bipolar) disorder Anxiety states including panic disorderand agoraphobia Post menstrual syndrome Schizophrenia Chronic fatiguesyndrome Substance abuse and drug addiction Anorexia nervosa andanorexia bullemia

TABLE III Examples of neurological/neurodegenerative disorders and CNSinflammatory disorders treatable using compounds described in thisinvention Migraine headaches (e.g. vascular headaches, common migraine)Primary (e.g. Alzheimer's disease) and secondary (e.g. HIV-related)dementias Degenerative CNS diseases (e.g. Parkinson's disease,amyotropic lateral sclerosis) Demyelinating diseases (e.g. multiplesclerosis, Guillain-Barre syndrome) Pain disorders including algesia,hyperalgesia, acute and chronic pain, allodynia Primary and secondaryencephalitis and encephalomyelitis (e.g. autoimmune encephalomyelitis,allergic encephalomyelitis) Primary and secondary neuritis, autoimmuneneuritis Other autoimmune diseases (e.g. myesthenia gravis,Eaton-Lambert syndrome) Congenital and secondary ataxias

TABLE IV Examples of inflammatory and metabolic disorders associatedwith allograft transplantation treatable using compounds described inthis invention The compounds described herein are useful as monotherapyor adjunctive therapy with existing immunosuppressive agents for thepromotion and maintenance of allograft survival, post-transplantation.Examples of inflammatory and proliferative conditions or diseasesassociated with allograft transplantation and immune suppressioninclude: 1. Acute allograft rejection 2. Chronic allograft rejection 3.Graft versus host disease 4. Post-transplantation de novo malignancy(e.g. lymphoma and epidermal cancers) 5. Osteoporosis and osteopenia 6.Hyperlipidemia 7. Insulin resistance and diabetes mellitus 8.Hypertension 9. Atherosclerosis 10. Endarteritis associated with heartallograft transplantation 11. Glomerulonephritis associated with renalallograft transplantation 12. Cardiomyopathy and congestive heartfailure associated with allograft transplantation, in particular hearttransplantation

TABLE V Examples of diseases of various organ systems treatable usingcompounds described in this invention Organ System Disease/PathologyCardiovascular Metabolic disorders including hypertension,vasculo-occlusive diseases including atherosclerosis, arteritis,endarteritis, endocarditis, myocarditis, arterial plaque (fibrous cap)rupture, thrombosis, restenosis after any invasive vascular procedures;acute coronary syndromes such as unstable angina, myocardial infarction,myocardial ischemia and other ischemic cardiomyopathies, non- ischemiccardiomyopathies, post-myocardial infarction cardiomyopathy andmyocardial fibrosis, drug-induced cardiomyopathy. Endocrine Metabolicdisorders including obesity, type 1 diabetes mellitus, type 2 diabetesmellitus, gestational diabetes, impaired glucose tolerance, Cushing'ssyndrome (e.g. secondary to chronic glucocorticoid therapy), polycysticovarian syndrome, osteoporosis, osteopenia, accelerated aging of tissuesand organs, e.g. Werner's syndrome. Urogenital Prostatitis,endometritis, endometriosis, benign prostatic hypertrophy, leiomyoma,polycystic kidney disease (e.g. autosomal dominant PKD), acute tubularnecrosis, nephrotic syndrome, diabetic nephropathy, glomerulonephritis,erectile dysfunction in men and women Pulmonary Asthma, chronicobstructive pulmonary disease (COPD), reactive airway disease, pulmonaryfibrosis, pulmonary hypertension. Connective Rheumatoid arthritis,Raynaud's phenomenon/disease, Sjogren's tissue syndrome, systemicsclerosis, systemic lupus erythematosus, Joint inflammatory boweldisease (ulcerative colitis, Crohn's disease) vasculitides, ankylosingspondylitis, osteoarthritis, reactive arthritis, psoriatic arthritis,fibromyalgia, osteoarthritis, sarcoidosis. Liver/Other Hepatic fibrosis,hepatic cirrhosis, hepatic steatosis, all etiologies, e.g.alcohol-induced (e.g. ethanol), drug-induced (e.g. tylenol), andtoxin-induced (e.g. mushroom poisoning) Fibrocystic breast disease,fibroadenoma, endometriosis

TABLE VIa Examples of neoplastic diseases treatable using compoundsdescribed in this invention Organ System Malignancy/Cancer type SkinBasal cell carcinoma, melanoma, squamous cell carcinoma; cutaneous Tcell lymphoma; Kaposi's sarcoma. Hematological Acute leukemia, chronicleukemia and myelodysplastic syndromes. Urogenital Prostatic, renal andbladder carcinomas, anogenital carcinomas including cervical, ovarian,uterine, vulvar, vaginal, and those associated with human papillomavirus infection. Neurological Gliomas including glioblastomas,astrocytoma, ependymoma, medulloblastoma, oligodendroma; meningioma,pituitary adenoma, neuroblastoma, craniopharyngioma. GastrointestinalColon, colorectal, gastric, esophageal, mucocutaneous carcinomas. BreastBreast cancer including estrogen receptor and progesterone receptorpositive or negative subtypes, soft tissue tumors. Metastasis Metastasesresulting from all neoplasms. Other Angiomata, angiogenesis associatedwith the neoplasms.

TABLE VIb Examples of neoplastic diseases treatable using compoundsdescribed in this invention (cont'd) Location Malignancy/Cancer typeVarious fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma,osteogenic sarcoma, chordoma, angiosarcoma, enthotheliosarcoma,lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelimoa,Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, basalcell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, andretinoblastoma.

TABLE VII Examples of viral infections and related pathologies treatableaccording to the methods of this invention Virus Viral infection/canceror other virus-associated pathology HTLV T-cell leukemia/lymphoma,HTLV-associated arthritides/myelopathies. HPV Cervical and anogenitalcancers; common and anogenital (venereal) warts, including verrucae,condyloma or condyloma acuminata, related non-neoplastic (e.g.,keratitis, conjunctivitis) pre-neoplastic and neoplastic (e.g.,conjunctival epithelial neoplasms) diseases of the eye. HAV, HBV,Hepatitis, hepatocellular carcinoma, lymphoma. HCV CMV Hepatitis,retinitis, meningitis. HSV, VSV Related mucocutaneous, oropharyngeal andgenital diseases, related skin and respiratory infections,varicella-zoster, chicken pox, herpes zoster, post- herpetic neuralgia,conjunctivitis, keratoconjunctivitis, keratitis. HHV Exanthem subitum,infectious mononucleosis. EBV Infectious mononucleosis, chronic fatiguesyndrome, lymphoma, conjunctivitis, keratitis, and related infections ofthe eye. Adenoviruses Upper and lower respiratory tract infections,pneumonia, conjunctivitis. RSV Upper and lower respiratory tractinfections, pneumonia. PMV Mumps and related manifestations, e.g.,conjunctivitis. MV, RV Measles, Rubella (“German measles”) and relatedmanifestations. Coxsackie Conjunctivitis, diabetes mellitus, respiratoryinfections. viruses Influenza Upper and lower respiratory tractinfections, pneumonia. virusesHIV, Human Immunodeficiency Virus; HTLV, Human T-cell Lymphocyte Virus;HPV, Human Papilloma Virus; HAV, Hepatitis A Virus; HBV, Hepatitis BVirus; HAV, Hepatitis C Virus; CMV, Cytomegalovirus; HSV, Herpes SimplexVirus (Types I & II); HHV, Human Herpes Virus; EBV, Epstein-Barr Virus;RSV, Respiratory Syncytial Virus; VZV, Varicella-Zoster Virus; PMV,Paramyxovirus; MV, Measles (Rubeola) Virus; RV, Rubella Virus

TABLE VIII HIV related infections and diseases treatable using compoundsdescribed in this invention Viral infection/manifestation Organ systemor other HIV-associated disease Immunologic AIDS, primary HIV infection.Dermatological Anogenital cancers including rectal and cervical cancer,Kaposi's sarcoma, atopic dermatitis, squamous cell carcinoma, hairyleukoplakia, molluscum contagiosum, warts (HPV infections), seborrheicdermatitis, psoriasis, xeroderma, HSV and varicella-zoster infections.Hematologic Non-Hodgkin's lymphoma, B cell lymphoma, anemia,neutropenia, thrombocytopenia. Gastrointestinal Anorexia, gastroparesis,diarrhea, malabsorption, gastrointestinal CMV infections, esophagitis,colitis, hepatitis, lymphoma. Ophthalmic Conjunctivitis, keratitis,keratoconjunctivitis, uveitis, retinitis, chorioretinitis, CMVretinitis, iridocyclitis, vitreitis, choroiditis, papilledema, Kaposi'ssarcoma, lymphoma, ocular palsies, conjunctival warts, pre- neoplasticand neoplastic diseases of the eye. Cardiac Myocarditis, endocarditis,pericarditis. Pulmonary CMV pneumonitis, lymphoid interstitialpneumonitis. Nephrologic HIV nephropathy, renal cell carcinoma,amyloidosis, uropathy. Rheumatologic Arthralgia, fibromyalgia, Reiter'ssyndrome, psoriatic arthritis, vasculitis. Neurologic Dementia, viralmeningitis, viral encephalitis, HIV encephalopathy, progressivemultifocal leukoencephalopathy, CNS lymphoma, peripheral and autonomicneuropathies. Psychiatric Dysphoric mood disorders, depression,depression associated with chronic diseases and medications, bipolardisorder, anxiety disorders, chronic fatigue syndrome, chronic pain,psychoses, substance abuse disorders and drug addiction. GeneralLymphoma, metastatic lymphoma, Kaposi's sarcoma, wasting syndrome,psychosis.

TABLE IXa Diseases of the eye treatable using compounds described inthis invention Disease Virus 1. Inflammatory eye diseases associatedwith viral infections Blepharitis HSV, VZV, Vaccinia, HPV, molluscumcontagiosum Conjunctivitis HSV, VZV, EBV, Adenovirus, Vaccinia, Variola,HPV, molluscum contagiosum, influenza Follicular c. Newcastle, measles,mumps, rubella, molluscum contagiosum Hemorrhagic c. Enterovirus,coxsackie Catarrhal c Rubella Keratitis HSV, VZV, EBV, Adenovirus,Vaccinia, Variola, HPV, molluscum contagiosum Keratoconjunctivitis HSV,VZV, EBV, Adenovirus, Vaccinia, Variola, HPV, molluscum contagiosumRetinitis CMV Uveitis HPV Conjunctival warts HPV Epithelial neoplasmsHPV 2. Oularplastic diseases Benign tumors Keratocanthoma, molluscumcontagiosum, dermoid cysts, neurofibroma, neurofibromatosis, schwannoma(neurilemoma), pleiomorphic adenoma Malignant tumors Basal cellcarcinoma, squamous cell carcinoma, mucoepidermoid carcinoma, melanoma,retinoblastoma, embryonal rhabdomyosarcoma, meningioma, adenoid cysticcarcinoma, lymphoid tumors of the orbit, mesenchymal tumors (fibroushystiocytoma) of the orbit, nasopharyngeal carcinoma. Vascular lesionsHemangioma, lymphangioma

TABLE XIb Ophthalmic diseases treatable using compounds described inthis invention (cont'd) Disease Category/Examples of Diseases, Causes orAssociated Conditions* Conjunctivitis Acute allergic conjunctivitis(e.g. drug-related inflammation, hypersensitivity reactions), chronic(vernal) conjunctivitis, contact lens-associated conjunctivitis, e.g.giant papillary conjunctivitis, conjunctival ulceration, includingulceration associated with mucous membrane, conjunctival wartsBlepharitis Inflammatory etiologies, e.g. blepharitis secondary torosacea Ophthalmic fibrosis Steven's-Johnson syndrome with progressivefibrosis and scarring, cicatrization and symblepharon. Corneal injuryCorneal abrasion or ulceration (e.g. contact lens-related injury), orcorneal injury of any etiology*. Dry eye syndrome See Table belowPterygium, pinguecula Pemphigoid Includes ophthalmic pemhigoriScleritis/Episcleritis Iridocyclitis Endophthalmitis Uveal tractdiseases Including glaucoma (primary and secondary etiologies) Uveitis,uveoretinitis, panuveitis, all etiologies* Vitreitis, retinitis e.g.congenital retinitis, retinitis pigmentosa Infectious retinitis Viral(e.g. herpes, cytomegalovirus, HIV), tuberculous, syphititic, fungal(e.g. histoplasmosis) Chorioretinopathies Chorioretinitis, choroiditis,vitreitis, Retinopathies e.g. Diabetic retinopathy, hypertensiveretinopathy Maculopathies age-related-macular degeneration, white dotsyndromes Cataract Related to diabetes, age, collagen vascular diseasesOcular palsies *Etiologies of ophthalmic diseases treatable according tothe methods of this invention include diseases induced or caused byphysical agents (e.g. UV radiation), chemical agents (e.g. acids,caustic solvents) immunological etiologies (e.g. collagen vasculardiseases, auto-immune, T lymphocyte-related), infectious agents such asviruses (HSV, CMV, HIV), mycoplasma, tuberculosis, syphilis, fungae(histoplasmosis)

TABLE IXc Ophthalmic diseases treatable using compounds described inthis invention (cont'd) - Etiologies of dry eye syndrome I. ConditionsCharacterized by Hypofunction of the Lacrimal Gland: A. CongenitalFamilial dysautonomia (Riley-Day syndrome), aplasia of the lacrimalgland (congenital alacrima), trigeminal nerve aplasia, ectodermaldysplasia B. Acquired 1. Systemic Diseases, e.g. Sjogren's Syndrome,progressive systemic sclerosis, sarcoidosis, leukemia, lymphyoma,amyloidosis, hemochromatosis, 2. Infection, e.g. mumps 3. Injury, e.g.surgical removal of lacrimal gland, irradiation, chemical burn 4.Medications, e.g. antihistamines, antimuscarinics (atropine,scopolamine), general anesthetics (halothane, nitrous oxide), ∃-adrenergic blockers (timolol, practolol), neurogenic, neuroparalytic(facial nerve palsy) II. Conditions Characterized by Mucin DeficiencyAvitaminosis A, Stevens-Johnson syndrome, ocular pemphigoid, chronicconjuncitivitis (e.g. trachoma), chemical burns, drugs and medicationsIII. Conditions Characterized by Lipid Deficiency Lid margin scarring,blepharitis IV. Defective Spreading of Team Film Caused by theFollowing: A. Eyelid abnormalities 1. Defects, colboma 2. Ectropion orentropion 3. Keratinization of lid margin 4. Decreased or absentblinking secondary to: neurologic disorders, hyperthyroidism, contactlens, drugs and medications, herpes simplex keratitis, leprosy,conjunctival abnormalities, pterygium, symblepharon, proptosis

TABLE IXd Ophthalmic diseases treatable using compounds described inthis invention (cont'd) - Non-hereditary and hereditary degenerativediseases Macular disorders: All etiologies and manifestations, includingage-related macular degeneration, exudative macular degeneration,atrophic macular degeneration, crystalline retinopathies, retinaltoxicosis of systemic medications, idiopathic central serouschoroidiopathy, macular edema Retinovascular diseases Retinopathy,vasculo-occlusive r., and retinopathies: ischemic r., idiopathic r.,hypertensive r., proliferative r., diabetic r., vitreoretinopathy,vasculopathies associated with telangiectasias or aneurysms,retinopathies associated with lupus erythematosus, rheumatoid arthritis,multiple sclerosis, myasthenia gravis, uveoretinitis or diabetesmellitus, glaucomatous retinopathies Glaucoma: All etiologies andmanifestations, including primary and secondary open- angle glaucoma,angle-closure glaucoma, glaucoma associated with intraocularinflammation, elevated intraocular pressure associated with acuteglaucoma, steroid-induced glaucoma, glaucoma associated with intraocularhemorrhage, pseudoexfoliative syndrome, glaucomatous optic neuropathyand other degenerative changes (e.g. retinopathy) associated withglaucoma Cataract: All etiologies and manifestations, includingage-related (UV radiation) cataract, cataract associated with systemicdiseases such as collagen vascular disease, diabetes mellitus, Wilson'sdisease Other diseases: Primary or secondary retinal detachment

TABLE IXe Ophthalmic diseases treatable using compounds described inthis invention (cont'd) - Congenital degenerative retinopathies I.Primary pigmented retinopathies, all gene types Autosomal dominantretinitis pigmentosa, e.g. rod-cone and cone-rod degenerations Autosomalrecessive retinitis pigmentosa, e.g. rod-cone and cone-roddegenerations, Lerner's amaurosis congenita X-linked recessive pigmentedretinopathies, e.g. choroideremia 2. Secondary pigmented retinopathies(retinopathies associated with systemic diseases) Autosomal dominantpigmented retinopathies, e.g. Paget's disease, Charcot-Marie-Tooth,disease, Steinert's disease, Pierre-Marie syndrome Autosomal recessivepigmented retinopathies, e.g. diabetes mellitus, mannosidoses,mucopolysccharidoses, Batten's d., Refsum's d., Usher syndrome X-linkedrecessive pigmented retinopathies, e.g. Hunter syndrome

TABLE X Diseases or conditions treatable using compounds described inthis invention I. Promote healing in the following clinical situations:Surgical or traumatic wounds to healthy tissues or organs Wounds causedby chemical or physical agents, e.g. ulcers caused by caustic or erosivechemicals, pressure sores, etc. Wounds associated with disease states,e.g. diabetic ulcers etc. Wounds in diseased tissues or organs II.Promote cell survival and prevent apoptosis in neurodegenerativediseases: Alzheimer's disease Parkinson's disease Amyotrophic lateralsclerosis Spinal cord ischemia, injury or transection secondary totrauma or disease III. Attenuation or arrest of the following conditionsor processes: The natural aging of cells and tissues Aging induced bychemical or physical agents, e.g. sun-induced skin aging Acceleratedaging associated with diseases, e.g. Werner's syndrome IV. Vitalizationand revitalization of organs and tissues Promoting cell growth andpreventing cell death in the aging process Promoting therapeutic ornon-pathological angiogenesis as a therapeutic approach to treatingdiseases such as congestive heart failure and cardiomyopathy Promotinggrowth of organs and tissues for repair or transplantation

The oral route of administration is the preferred mode for treatment orprevention of type 2 diabetes, the metabolic syndrome, and most otherchronic disorders. Therapeutic agents of the invention are usuallydelivered or administered topically for treating disorders involving theeye or the skin except in some cases where oral administration is thepreferred mode. Additionally, the agents can be delivered parenterally,especially for treatment of retinitis and degenerative retinal diseases,and for other conditions in Tables I through X, that do not respond tooral or topical therapy, or for conditions where oral or topical therapyis not feasible. Parenteral therapy is typically oral, intraocular,transcutaneous, intradermal, intrathecal, intramuscular,intra-articular, by inhalation, intravascular, sublingual, bysuppository (e.g. per-rectum or vaginal application), by inhalation, orother parenteral route.

A preferred way to practice the invention for dermatological orophthalmic disorders in Tables I through X to which this method isapplicable, is to apply the compound of interest, in a cream, lotion,ointment, or oil based carrier, directly to the lesion. Typically, theconcentration of therapeutic compound in a cream, lotion, or oil is 0.1to 2.5%. In general, the preferred route of administration is oral,topical, intraocular or parenteral. Topical administration is preferredin treatment of lesions of the skin as in psoriasis, external eye as inconjunctivitis, keratitis, scleritis, squamous cell carcinoma, cornealerosion, dry eye syndrome, and anterior compartment of the eye as inglaucoma, uveitis and other diseases of the uveal tract, where suchdirect application is practical and clinically indicated.

Oral administration is a preferred alternative for treatment of otherlesions discussed in Tables I through X, where direct topicalapplication is not useful as in the treatment of chronic or acutesystemic diseases, and diseases of the posterior segment of the eye, asin retinitis and other retinal degenerative diseases. Intravascular(intravenous being the preferred route) administration may be necessaryin disorders that cannot be effectively treated by topical or oraladministration.

Intraocular, transcutaneous, intradermal, intrathecal, intramuscular,intra-articular injections or other invasive technique are preferredalternative in cases where the practitioner wishes to treat one or a fewspecific areas or lesions depending on their location within the eye.Usually, the compound is delivered in an aqueous solution. Additionally,the therapeutic compounds are injected directly into lesions(intra-lesion administration) in appropriate cases. Intradermaladministration is an alternative for extraocular lesions. Intra-lesionaland intradermal injections are alternative routes of application forcertain lesions, e.g. extraocular neoplastic or hyperplastic lesionssuch as squamous cell carcinoma and condyloma, respectively. Inhalationtherapy is preferred for pulmonary diseases, sublingual and intra-rectalsuppository is preferred for rapid delivery or in clinical situationswhere delivery via the oral or intravascular route is inconvenient orproblematic. Application via vaginal topical formulation or viasuppository formulation is preferred for diseases localized to thevagina or other segment of the urogenital tract.

An effective quantity of the compound of interest is employed intreatment. The dosage of compounds used in accordance with the inventionvaries depending on the compound and the condition being treated. Forexample, the age, weight, and clinical condition of the recipientpatient; and the experience and judgment of the clinician orpractitioner administering the therapy are among the factors affectingthe selected dosage. Other factors include: the route of administration,the patient, the patient's medical history, the severity of the diseaseprocess, and the potency of the particular compound. The dose should besufficient to ameliorate symptoms or signs of the disease treatedwithout producing unacceptable toxicity to the patient.

In general, an effective amount of the compound is that which provideseither subjective relief of symptoms or an objectively identifiableimprovement as noted by the clinician or other qualified observer. Atypical oral dose is between 1 mg per day up to 1000 mg per dayaccording to the judgment of the clinician. Typically, the dosage perday of the compounds of this invention will depend on the their abilityto activate PPARgamma and their ability to block the angiotensin II type1 receptor. The dosages of these compounds will generally run between0.1 mg to 1000 mg per day with a common dose being 5mg per day to 300 mgper day. Typically, the greater the ability to activate PPARgamma and toblock the angiotensin II receptor, the more effective the compound, andthe lower the dosage that is an effective amount.

An oral dosing schedule is typically, a single dose once a day. However,more than one dose can be given per day. Because of the lower incidenceof undesirable side effects, the compounds of this invention can begiven until improvement in the disorder of interest is observed andcontinued as necessary to maintain such an improved clinical state. Thecompounds may or may not be administered with food or with other agentsdepending on how food or other agents affects their absorption by thebody and depending on the judgment of those skilled in the therapeuticart.

The dosage can be administered once or twice a day, but the cliniciancan recommend more or less frequent dosing. Once a therapeutic result isachieved, the compound can be tapered or discontinued or continuedaccording to the recommendation of the clinician. Occasionally, sideeffects warrant discontinuation of therapy.

An effective quantity of the compound of interest is employed intreatment. The dosage of compounds used in accordance with the inventionvaries depending on the compound and the condition being treated. Theage, lean body weight, total weight, body surface area, and clinicalcondition of the recipient patient; and the experience and judgment ofthe clinician or practitioner administering the therapy are among thefactors affecting the selected dosage. Other factors include the routeof administration the patient, the patient's medical history, theseverity of the disease process, and the potency of the particularcompound. The dose should be sufficient to ameliorate symptoms or signsof the disease treated without producing unacceptable toxicity to thepatient.

Broadly, an oral dosing schedule is from about 0.1 mg to about 1000 mgonce or twice a day. Using telmisartan as the prototype agent for thepurpose of this invention, a convenient oral dose for an adult patientis approximately 80 mg to 160 mg per day but could be less or moredepending on the indication. A dosage range for topical treatment isabout 0.1% to about 1% (weight/volume) in a gel, cream or ointment,applied twice a day. A usual dose for intramuscular or intraocularinjection is 0.25 to 2.5 mg, depending on the compartment of the eye tobe treated and on the lean body mass of the patient. A typical dosagefor intra-dermal administration is about 2.5 to 25 mg per injection persite. A typical dosage for intravenous or intramuscular administrationin an adult patient would be between 50 and 250 mg per day given insingle or divided doses depending on the judgment of the practitioner.

Compounds and Formulations of the Invention

Compounds useful for the application of methods described in thisinvention include all existing synthetic and naturally occurring agentsthat both increase the activity of PPARgamma and block or antagonize theactivity of the angiotensin II type 1 receptor as well as those yet tobe discovered that have such dual ability. Preferred compounds for thepurposes of this invention include telmisartan (Micardis®), irbesartan(Avapro®) as well as any derivatives or formulations thereof and any newARBs that may be marketed in the future that have the ability toactivate PPARgamma.

For oral administration, either solid or fluid unit dosage forms can beprepared. For preparing solid compositions such as tablets, the compoundof interest is mixed into formulations with conventional ingredientssuch as talc, magnesium stearate, dicalcium phosphate, magnesiumaluminum silicate, calcium sulfate, starch, lactose, acacia,methylcellulose, and functionally similar materials as pharmaceuticaldiluents or carriers. Capsules are prepared by mixing the compound ofinterest with an inert pharmaceutical diluent and filling the mixtureinto a hard gelatin capsule of appropriate size. Soft gelatin capsulesare prepared by machine encapsulation of a slurry of the compound ofinterest with an acceptable vegetable oil, light liquid petrolatum orother inert oil. Fluid unit dosage forms for oral administration such assyrups, elixirs and suspensions can be prepared. The water-soluble formscan be dissolved in an aqueous vehicle together with sugar, aromaticflavoring agents and preservatives to form a syrup. An elixir isprepared by using a hydroalcoholic (e.g., ethanol) vehicle with suitablesweeteners such as sugar and saccharin, together with an aromaticflavoring agent. Suspensions can be prepared with an aqueous vehiclewith the aid of a suspending agent such as acacia, tragacanth,methylcellulose and the like.

Appropriate formulations for parenteral use are apparent to thepractitioner of ordinary skill. Usually, the therapeutic compound isprepared in an aqueous solution (discussed below) in a concentration offrom about 1 to about 100 mg/ml. More typically, the concentration isfrom about 10 to 60 mg/ml or about 20 mg/ml. Concentrations below 1mg/ml may be necessary in some cases depending on the solubility andpotency of the compound selected for use. The formulation, which issterile, is suitable for various topical or parenteral routes includingsublingual, by suppository (e.g. per-rectum or vaginal application),oral, intravascular, intradermal, by inhalation, intramuscular,intra-articular, intravenous, or other parenteral route.

In addition to the therapeutic compound, the compositions may include,depending on the formulation and mode of delivery desired,pharmaceutically-acceptable, non-toxic carriers or diluents, whichinclude vehicles commonly used to form pharmaceutical compositions foranimal or human administration. The diluent is selected so as not tounduly affect the biological activity of the combination. Examples ofsuch diluents which are especially useful for injectable formulationsare water, the various saline, organic or inorganic salt solutions,Ringer's solution, dextrose solution, and Hank's solution. In addition,the pharmaceutical composition or formulation may include additives suchas other carriers; adjuvants; or nontoxic, nontherapeutic,nonimmunogenic stabilizers and the like.

Furthermore, excipients can be included in the formulation. Examplesinclude cosolvents, surfactants, oils, humectants, emollients,preservatives, stabilizers and antioxidants. Any pharmacologicallyacceptable buffer may be used, e.g., tris or phosphate buffers.Effective amounts of diluents, additives and excipients are thoseamounts which are effective to obtain a pharmaceutically acceptableformulation in terms of solubility, biological activity, etc.

The term “unit dosage form” refers to physically discrete units suitableas unitary dosages for human subjects and animals, each unit containinga predetermined quantity of active material calculated to produce thedesired pharmaceutical effect in association with the requiredpharmaceutical diluent, carrier or vehicle. The specifications for theunit dosage forms of this invention are dictated by and dependent on (a)the unique characteristics of the active material and the particulareffect to be achieved and (b) the limitations inherent in the art ofcompounding such an active material for use in humans and animals.Examples of unit dosage forms are tablets, capsules, pills, powderpackets, wafers, suppositories, granules, cachets, teaspoonfuls,tablespoonfuls, dropperfuls, ampoules, vials, aerosols with metereddischarges, segregated multiples of any of the foregoing, and otherforms as herein described.

Thus, a composition of the invention includes a therapeutic compoundwhich may be formulated with conventional, pharmaceutically acceptable,vehicles for topical, oral or parenteral administration. Formulationsmay also include small amounts of adjuvants such as buffers andpreservatives to maintain isotonicity, physiological and pH stability.Means of preparation, formulation and administration are known to thoseof skill. See generally Remington's Pharmaceutical Science 15th ed.,Mack Publishing Co., Easton, Pa. (1980).

To prepare a topical formulation for the treatment of ophthalmologicalor dermatological or other disorders listed in Tables I through X, atherapeutically effective concentration of the compound is placed in adermatological vehicle as is known in the art. The amount of thetherapeutic compound to be administered and the compound's concentrationin the topical formulations depend upon the vehicle, delivery system ordevice selected, the clinical condition of the patient, the side effectsand the stability of the compound in the formulation. Thus, thephysician employs the appropriate preparation containing the appropriateconcentration of the therapeutic compound and selects the amount offormulation administered, depending upon clinical experience with thepatient in question or with similar patients.

The therapeutic compound is optionally administered topically by the useof a transdermal therapeutic system (see Barry, DermatologicalFormulations, (1983) p. 181 and literature cited therein). While suchtopical delivery systems have been designed largely for transdermaladministration of low molecular weight drugs, by definition they arecapable of percutaneous delivery. They may be readily adapted toadministration of the therapeutic compounds of the invention byappropriate selection of the rate-controlling microporous membrane.

For ophthalmic applications the therapeutic compound is formulated intosolutions, suspensions, and ointments appropriate for use in the eye.The concentrations are usually as discussed above for topico-localpreparations. For ophthalmic formulations, see Mitra (ed.), OphthalmicDrug Delivery Systems, Marcel Dekker, Inc., New York, N.Y. (1993) andalso Havener, W. H., Ophthalmic Pharmacology, C.V. Mosby Co., St. Louis(1983).

The concentration of the therapeutic compound used depends on the modeof delivery. For topical ophthalmic and extraocular formulations, theconcentration of the therapeutic compound is in the range of about 0.01%weight/weight (w/w) to about 10% w/w. Typically, the concentration ofthe therapeutic compound for this mode of delivery is in the range ofabout 0.025% w/w to about 2.5% w/w. Solid dispersions of the therapeuticcompound as well as solubilized preparations can be used. Forintraocular formulations (chemical delivery or delivery by invasivedevice), the therapeutic compound is delivered at a concentration highenough to achieve a final concentration in the range of about 0.1:mol/Lto about 10:mol/L within the target ophthalmic compartment (e.g. theposterior chamber for the treatment of retinal diseases). Typically, forthis mode of delivery, the final concentration of the therapeuticcompound is in the range of about 0.25:mol/L to about 5:mol/L. Soliddispersions of the therapeutic compound as well as solubilizedpreparations can be used. Thus, the precise concentration is subject tomodest but not undue experimental manipulation well within the skill ofthe ordinary medical practitioner in order to optimize the therapeuticresponse. Suitable vehicles include oil-in-water or water-in-oilemulsions for preparation of ointments using mineral oils, petrolatum,lanolin, glycerin and the like as well as gels such as hydrogel. Apreferred embodiment of the present invention involves administration ofsemi-solid or solid implants containing PPARgamma agonists.

Slow or extended-release delivery systems, including any of a number ofbiopolymers (biological-based systems), systems employing liposomes,colloids, resins, and other polymeric delivery systems orcompartmentalized reservoirs, can be utilized with the compositionsdescribed herein to provide a continuous or long term source oftherapeutic compound. Such slow release systems are applicable toformulations for delivery via topical, intraocular, oral, and parenteralroutes.

As mentioned above, delivery intravascularly, intra-articularly,intramuscularly, intra-articularly, intradermally, or other parenteralroute can be accomplished by injection, cannula or other invasive devicedesigned to introduce precisely metered amounts of a desired formulationto a particular compartment or tissue. For example, delivery to certainareas within the eye, in situ, can be accomplished by injection, cannulaor other invasive device designed to introduce precisely metered amountsdirectly or contained in a reservoir for slow release in situ, of adesired formulation to a particular compartment or tissue within the eye(e.g. anterior or posterior chamber, uvea or retina). Preferably, asolid or semisolid implant can be delivered subretinally using theinstrumentation and methods described in U.S. Pat. No. 5,817,075 andU.S. Pat. No. 5,868,728.

Combination Use of Drugs

A compound according to the present invention may be used in combinationwith a diabetes mellitus-treating agent, a diabeticcomplication-treating agent, an antihyperlipemic agent, a hypotensive orantihypertensive agent, an anti-obesity agent, a diuretic, achemotherapeutic agent, an immunotherapeutic agent, andimmunosuppressive agent, and the like (hereinafter referred to as aconcomitant agent). In such case, the periods of the treatments with acompound according to the present invention and with a concomitant agentare not limited particularly, and such agents may given to a patientsimultaneously or at a certain time interval. The dose of a concomitantdrug may appropriately be determined based on the customary clinicaldose. The ratio between a compound according to the present inventionand a concomitant agent may be appropriately determined based on variousfactors such as the subject to be treated, the administration route, thedisease or the condition to be treated and the combination of the drugs.For example, when a human is treated, 1 parts by weight of a compoundaccording to the present invention is combined with 0.01 to 100 parts byweight of a concomitant agent.

Examples of an agent for treating diabetes mellitus are an insulinformulation (e.g., animal insulin formulations extracted from a pancreasof a cattle or a swine; a human insulin formulation synthesized by agene engineering technology using microrganisms or methods), an insulinsensitivity enhancing agent (e.g., pioglitazone hydrochloride,troglitazone, rosiglitazone and the like), an alpha-glycosidaseinhibitor (e.g., voglibose, acarbose, miglitol, emiglitate and thelike), a biguanide (e.g., phenformin, metformin, buformin and the like),or a sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide,chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepirideand the like) as well as other insulin secretion-promoting agents (e.g.,repaglinide, senaglinide, nateglinide, mitiglinide, GLP-1 and the like),amyrin agonist (e.g. pramlintide and the like),phosphotyrosinphosphatase inhibitor (e.g. vanadic acid and the like) andthe like.

Examples of an agent for treating diabetic complications are an aldosereductase inhibitor (e.g., tolrestat, epalrestat, zenarestat,zopolrestat, minalrestat, fidareatat, SK-860, CT-112 and the like), aneurotrophic factor (e.g., NGF, NT-3, BDNF and the like), PKC inhibitor(e.g. LY-333531 and the like), AGE inhibitor (e.g. ALT946, pimagedine,pyradoxamine, phenacylthiazolium bromide (ALT766) and the like), anactive oxygen quenching agent (e.g., thioctic acid or derivativethereof, a bioflavonoid including flavones, isoflavones, flavonones,procyanidins, anthocyanidins, pycnogenol, lutein, lycopene, vitamins E,coenzymes Q, and the like), a cerebrovascular dilating agent (e.g.,tiapride, mexiletene and the like).

An antihyperlipemic agent may for example be a statin-based compoundswhich is a cholesterol synthesis inhibitor (e.g., pravastatin,simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin and thelike), a squalene synthetase inhibitor or a fibrate compound having atriglyceride-lowering effect (e.g., gemfibrozil, bezafibrate,clofibrate, sinfibrate, clinofibrate and the like).

A hypotensive agent may for example be an angiotensin converting enzymeinhibitor (e.g., captopril, enalapril, delapril, benazepril, cilazapril,enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril,quinapril, ramipril, trandolapril, and the like) or an angiotensin IIantagonist (e.g., losartan, candesartan cilexetil, eprosartan,valsartan, telmisartan, irbesartan, tasosartan and the like).

An antiobesity agent may for example be a central antiobesity agent(e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine,amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorexand the like), a pancreatic lipase inhibitor (e.g., orlistat and thelike), β-3 agonist (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552,AJ-9677, BMS-196085 and the like), a peptide-based appetite-suppressingagent (e.g., leptin, CNTF and the like), a cholecystokinin agonist(e.g., lintitript, FPL-15849 and the like) and the like.

A diuretic may for example be a xanthine derivative (e.g., theobrominesodium salicylate, theobromine calcium salicylate and the like), athiazide formulation (e.g., ethiazide, cyclopenthiazide,trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,bentylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazideand the like), anti-aldosterone formulation (e.g., spironolactone,triamterene and the like), a decarboxylase inhibitor (e.g.,acetazolamide and the like), a chlorbenzenesulfonamide formulation(e.g., chlorthalidone, mefruside, indapamide and the like), azosemide,isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and thelike.

A chemotherapeutic agent may for example be an alkylating agent (e.g.,cyclophosphamide, iphosphamide and the like), a metabolism antagonist(e.g., methotrexate, 5-fluorouracil and the like), an anticancerantibiotic (e.g., mitomycin, adriamycin and the like), avegetable-derived anticancer agent (e.g., vincristine, vindesine, taxoland the like), cisplatin, carboplatin, etoposide and the like. Amongthese substances, 5-fluorouracil derivatives such as furtulon andneofurtulon are preferred.

An immunotherapeutic agent may for example be a microorganism orbacterial component (e.g., muramyl dipeptide derivative, picibanil andthe like), a polysaccharide having immune potentiating activity (e.g.,lentinan, sizofilan, krestin and the like), a cytokine obtained by agene engineering technology (e.g., interferon, interleukin (IL) and thelike), a colony stimulating factor (e.g., granulocyte colony stimulatingfactor, erythropoetin and the like) and the like, among thesesubstances, those preferred are IL-1, IL-2, IL-12 and the like.

An immunosuppressive agent may for example be a calcineurininhibitor/immunophilin modulator such as cyclosporine (Sandimmune,Gengraf, Neoral), tacrolimus (Prograf, FK506), ASM 981, sirolimus (RAPA,rapamycin, Rapamune), or its derivative SDZ-RAD, a glucocorticoid(prednisone, prednisolone, methylprednisolone, dexamethasone and thelike), a purine synthesis inhibitor (mycophenolate mofetil, MMF,CellCept(R), azathioprine, cyclophosphamide), an interleukin antagonist(basiliximab, daclizumab, deoxyspergualin), a lymphocyte-depleting agentsuch as antithymocyte globulin (Thymoglobulin, Lymphoglobuline),anti-CD3 antibody (OKT3), and the like.

In addition, an agent whose cachexia improving effect has beenestablished in an animal model or at a clinical stage, such as acyclooxygenase inhibitor (e.g., indomethacin and the like) [CancerResearch, Vol.49, page 5935-5939, 1989], a progesterone derivative(e.g., megestrol acetate) [Journal of Clinical Oncology, Vol. 12, page213-225, 1994], a glucosteroid (e.g., dexamethasone and the like), ametoclopramide-based agent, a tetrahydrocannabinol-based agent (supra),a lipid metabolism improving agent (e.g., eicosapentanoic acid and thelike) [British Journal of Cancer, Vol. 68, page 314-318, 1993], a growthhormone, IGF-1, or an antibody against TNF-.alpha., LIF, IL-6,oncostatin M which are cachexia-inducing factors may also be employedconcomitantly with a compound according to the present invention.

The possible preferred combinations of the agents for the preventionand/or treatment of diabetes are, a PPARgamma activator with ARBactivity, and:

-   1) an insulin formulation and a biguanide;-   2) a sulfonylurea agent and a biguanide;-   3) a sulfonylurea agent and an alpha-glycosidase inhibitor;-   4) a biguanide and an alpha-glycosidase inhibitor;-   5) a blood sugar reducing agent and the other kind of agents for    treating diabetic complications;-   6) an 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase    inhibitor;-   7) any other two kinds of agents mentioned above.-   8) an agent that inhibits activity of angiotensin converting enzyme

In case that the compound or the composition of the present invention isused in combination with the other agent, an amount of each other agentcan be reduced in a range which is safe in light of its adverse effect.Especially, an insulin sensitivity enhancing agent, a biguanide and asulfonylurea agent can be used in less dose than regular dose so thatadverse effects which may be caused by these agents can be safelyavoided. In addition, an agent for treating diabetic complications, anantihyperlipemic agent and a hypotensive agent can also be used in lessdose, so that adverse effect which may be caused by them can be avoidedeffectively.

As noted above, by administering both an ARB and a PPAR activatorformulated together in a single pill or tablet, one can also treatglucose intolerance or type 2 diabetes and other PPAR responsivedisorders without causing fluid retention, edema, or congestive heartfailure. For this purpose, one can prepare and use a pharmaceuticalcomposition comprising: (i) a PPAR activator in a therapeuticallyeffective amount sufficient to prophylactically prevent, slow, delay ortreat a metabolic, inflammatory, atopic, autoimmune, proliferative, orcardiovascular disorder in humans; (ii) an angiotensin II type 1receptor antagonist in a therapeutically effective amount sufficient toprevent, slow, delay, or treat fluid retention, peripheral edema,pulmonary edema, or congestive heart failure; and (iii) apharmaceutically acceptable carrier. For this purpose, the PPARactivator in the pharmaceutical composition can be is athiazolidinedione selected from the group of compounds consisting ofrosiglitazone, pioglitazone, KRP 297, MCC-555, netoglitazone,rivoglitazone and balagitazone, or an analog thereof, or a tautomericform thereof, or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof. Alternatively, the PPARactivator in the pharmaceutical composition can be anon-thiazolidinedione selected from the group of compounds consisting oftesaglitazar, farglitazar, ragaglitazar, LY818, T131, LSN862, DRF 4832,LM 4156, LY 510929, LY 519818, TY 51501, X 334, or an analog thereof, ora tautomeric form thereof, or a pharmaceutically acceptable saltthereof, or a pharmaceutically acceptable solvate thereof. Otherthiazolidinedione or non-thiazolidinedione activators of PPARs that arefamiliar to those skilled in the art can also be employed. For purposesof making the pharmaceutical composition, the angiotensin II type 1receptor antagonist can be a compound selected from the group consistingof telmisartan, irbesartan, valsartan, losartan, candesartan,candesartan cilexetil, olmesartan, olmesartan medoximil, losartan,valsartan, eprosartan, irbesartan, tasosartan, pomisartan, ripisartan,and forasartan, or an analog thereof, or a tautomeric form thereof, or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof.

The compounds in this invention can also be given orally in combinationwith natural or synthetic compounds that bind to or modify the activityof the vitamin D receptor or other nuclear hormone receptor or incombination with compounds that bind to or modify the activity of theretinoid X receptor to provide for a synergistic effect in the treatmentor prevention of the disorders listed in Tables I through X. Examples ofsuch compounds that provide for synergistic effect when given incombination with the drugs encompassed by the current invention includevitamin D analogs, various retinoic acid derivatives, and other ligandsfor retinoid X receptors or retinoic acid receptors including but notlimited to compounds such as LG100268, tazarotene, TTNPB, AGN 190121,adapalene or LGD1069 (Targretin).

Synergistic therapeutic effects can be achieved by oral or topicaladministration of the drugs encompassed in the current inventiontogether with orally, topically or intravenously administered drugs thatbind to and modify the activity of either the vitamin D receptor, theglucocorticoid receptor, the intracellular enzyme calcineurin, theretinoid X receptors, the retinoic acid receptors, or other PPARs suchas PPARalpha or PPARdelta. A preferred dosage range for administrationof a retinoic acid derivative or retinoid would typically be from 0.1 to100 mg per square-meter of body surface area, depending on the drug'sability to bind to or modify the activity of its cognate nuclearreceptor, given in single or divided doses, orally or by continuousinfusion, two or three times per day. For synergistic therapy, thepreferred dosages and routes and frequency of administration of thevitamin D analogs or retinoid compounds can be similar to the dosagesand routes and frequency of administration ordinarily recommended forthese agents when given without PPAR activators. Examples of effectiveretinoids are 9-cis-retinoic acid, 13-cis-retinoic acid,all-trans-retinoic acid (at-RA). Preferred retinoids for this purposewould include 13-cis-retinoic acid, tazarotene, or Targretin. Apreferred dosage range for systemic administration of a vitamin D analogwould typically be from 0.1 to 100 mg per square-meter of body surfacearea, depending on the drug's ability to bind to and or activate itscognate vitamin D receptor, given in single or divided doses, orally orby continuous infusion, two or three times per day. Examples ofeffective vitamin D analogs are 1,25-dihydroxy-vitamin D, calcipotrieneand calcipotriol. The dosage range and routes and frequency ofadministration of PPAR activators required to achieve synergisticeffects when given with vitamin D or retinoid derivatives are the sameas those described elsewhere in this disclosure. The preferred mode ofadministration of these drugs for synergistic therapeutic purposes wouldbe orally although alternatively one can use topical or parenteralroutes of administration. The dosages and the modes and frequency ofadministration of the vitamin D or retinoid related compounds forsynergistic topical therapy would be similar to those ordinarilyrecommended for these agents when given without PPAR activators. Thedosage range and the modes and frequency required for topicaladministration of the flavonoid thiazolidine derivatives given incombination with vitamin D or retinoid related compounds are the same asthose described elsewhere in this disclosure.

Synergistic therapeutic effects can be achieved by oral or topicaladministration of the drugs encompassed in the current inventiontogether with orally, topically or intravenously administered natural orsynthetic antioxidants. These include ascorbic acid and its derivatives(e.g. vitamin C), the tocopherols (e.g. vitamin E, vitamin E succinate),carotenes and carotenoids (e.g. β-carotene), alpha-lipoic acid,probucols, flavones, isoflavones and flavonols (e.g. quercetin,genistein, catechin, apigenin, lutein, luteolin), lycopene, pycnogenol,glutathione and its derivatives (e.g. N-acetylcysteine anddithiothreitol), and phytoestrogens and phenolic anthocyanidin andprocyanidin derivatives (e.g. resveratrol, cyanidin, cinnamic acid).

The compounds of the instant invention are further useful to suppressthe mediators of neurogenic inflammation (e.g. substance P or thetachykinins), and may be used in the treatment of rheumatoid arthritis;psoriasis; topical inflammation such as is associated with sunburn,eczema, or other sources of itching; and allergies, including asthma.The compounds can also function as neuromodulators in the centralnervous system, with useful applications in the treatment of Alzheimer'sdisease and other forms of dementia, pain (as a spinal analgesic), andheadaches. Furthermore, in disorders involving myocardial fibrosis,myocardial ischemia, pathological conditions secondary to the autoimmuneresponse to allograft transplantation, the splanchnic blood flow,including hepatic fibrosis, cirrhosis and esophageal varices, thecompounds of the invention can provide cytoprotection.

The present invention is further detailed in the following Examples andMethods which are not intended to restrict the present invention.

Method for Designing and Identifying an ARB as a PPAR Ligand

ARBs, or derivatives thereof, may be tested for their ability toactivate the various PPAR isoforms by utilizing standard screeningmethods known to those skilled in the art including but not limited tocell based transactivation assays or cell free assays that test theability of a compound to activate a PPAR construct by measuring theoutput of a reporter signal that reflects the extent of the PPARactivation. For example, the angiotensin receptor blocker telmisartan isadded to the culture media of CV1 cells or other cells that can betransfected with a full length or partial PPAR cDNA sequence togetherwith a reporter construct containing a PPAR response element or otherappropriate response element fused to a reporter gene such asluciferase. The ability of telmisartan to activate PPARgamma is testedby measuring the luciferase reporter gene activity and it is found thattelmisartan causes a significant increase in reporter gene activity wellabove the background level present in the cells not treated withtelmisartan. Similar experiments are performed with irbesartan which isalso found to activate PPARgamma. Any ARBs found to activate PPARgammaaccording to these or other methods, can be used to treat disordersknown to be responsive to PPAR activators.

One can also make chemical modifications to existing ARBs that can bepredicted to enhance their ability to activate PPARgamma. Therefore, onecan design ARBs that are particularly effective in treating disordersknown to be responsive to PPAR activators without causing fluidretention, edema, or congestive heart failure. One can also modifychemical structures of PPAR activators to enhance their ability toinhibit ACE activity or block angiotensin receptors. This can beaccomplished using published information on the crystal structures ofthe PPARs and published information on the amino acid residues andregions of the PPARs that are important in receptor activation togetherwith known methods for testing ability of compounds to inhibit ACEactivity or block angiotensin receptors. Using methods known to thoseskilled in the art, one can make chemical modifications to existing ARBsor ACE inhibitors or design derivatives thereof that can be predicted tohave improved ability to activate PPARs than existing ARBs or ACEinhibitors.

Method of Identifying a PPAR Ligand with Decreased Risk for CausingFluid Retention, Edema, or Congestive Heart Failure

One can identify PPARgamma activators that have improved safety profileand decreased risk for causing fluid retention, edema, or congestiveheart failure by testing their ability to inhibit angiotensin convertingenzyme activity or their ability to block the angiotensin receptor.PPARgamma ligands or PPARgamma activators that also inhibit ACE activityor block angiotensin II type 1 receptors represent an improvement overexisting PPAR ligands for treating PPAR responsive disorders becausethey have reduced likelihood of causing fluid retention, edema, orcongestive heart failure. A variety of assays are available that can beused by those skilled in the art to determine whether a PPARgammaactivator can also block the angiotensin II type 1 receptor or inhibitthe activity of angiotensin converting enzyme. According to the methodof Groff J L, et al. (Simplified enzymatic assay ofangiotensin-converting enzyme in serum. Clin Chem. 1993; 39:400-4) orother assays that are familiar to those skilled in the art of testingcompounds for their ability to inhibit angiotensin converting enzymeactivity.

The ability of a PPAR ligand to selectively block the interaction ofangiotensin II (AII) with the angiotensin II type 1 receptor can bedetermined by the method of competitive binding of radiolabelledangiotensin II to preparations enriched in the AII type 1 receptor vs.the AII type 2 receptor. Other methods that are familiar to thoseskilled in the art of identifying compounds that block the angiotensinII type 1 receptor can also be used to determine whether a PPARactivator can block the angiotensin II type 1 receptor to any degreewhich would be useful in identifying a PPAR activator that is unlikelyto cause fluid retention, edema, or congestive heart failure.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all and onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Celsius, andpressure is at or near atmospheric.

Example 1 Identification of Angiotensin II type 1 Receptor Blockers thatActivate PPARgamma

PPARγ activity was determined by transactivation assays in CV-1 cells(CCL-70 line from ATCC, Bethesda, Md.) transfected using the GenePortertransfection reagent (Gene Therapy Systems, San Diego, Calif.) todeliver 200 ng of a PPARγ expression plasmid and 1 μg of a luciferasereporter plasmid and 400 ng pCMVSport β-gal (Gibco, Grand Island, N.J.)as an internal control. 24 hr post-transfection, cells were treated withvarying concentrations of the test compounds (telmisartan, irbesartan,valsartan, losartan, the active metabolite of losartan, the active formsof candesartan and olmesartan, rosiglitazone, or pioglitazone) andincubated for an additional 24 hr. Cell extracts were assayed forluciferase and β-galactosidase activity using Promega (Madison, Wis.)assay systems. All treatments were performed in triplicate, andnormalized for β-galactosidase activity. Agonist concentrations yieldinghalf maximal activation (EC₅₀ values) were calculated using GraphPadPrism version 3.03 (GraphPad Software, Inc., San Diego, Calif.).

Telmisartan significantly activated PPARγ (5-8 fold) when tested atconcentrations (1-5 μM) that can be achieved in plasma with conventionaloral dosing [Stangier, 2000 #14424]. Telmisartan functioned as amoderately potent (EC₅₀=5.6 μM), PPARγ agonist, activating the receptorto 25%-30% of the maximum level of activity achieved by the fullagonists pioglitazone and rosiglitazone. Irbesartan activated PPARγ (2-3fold activation) when tested at 10 μM. None of the other ARBs testedcaused any significant activation of PPAR even when tested at higherconcentrations (more than 10 μM). These experiments demonstrate that twoknown angiotensin receptor blockers, telmisartan and irbesartan, arealso activators of PPARgamma. Because PPARgamma activators can be usedto treat and prevent type 2 diabetes, the metabolic syndrome, and otherclinical disorders responsive to treatment with PPAR activators, theseexperiments demonstrate the utility of telmisartan and irbesartan forthe prevention and treatment of type 2 diabetes, the metabolic syndrome,and other disorders known to be responsive to treatment with PPARactivators.

Example 2 Measurement of In Vitro Adipocyte Differentiation Activity

The following examples 2 and 3 provide a generic means to measureadipocyte differentation to determine if one has an insulin-sensitizingagent. A mouse preadipocyte cell line (3T3-L1) obtained from theAmerican Type Culture Collection, and the cells are grown in aDulbecco's modified Eagle medium (DMEM) containing 4.5 g/L glucose, 50mg/L streptomycin sulfate, 100,000 units/L penicillin-G, 0.584 g/LL-glutamine, 4 mg/L pantothenate, 8 mg/L D-biotin, and 10 mM HEPES (pH7.2)] supplemented with 10% fetal bovine serum (FBS). The cells are thenplated at 1.5×104/cm² in a 96-well tissue culture plate (view plate, 96white, Packard) coated with type 1 collagen. After the cells had reachedconfluence, the cells were further cultured with differentiation mediumDMEM supplemented with 5% FBS, 100 ng/mL insulin, 0.1 mMisobutylmethylxanthine (IBMX), and 1 mM dexamethasone, and containingvarious concentrations of compounds for 4 days. The compounds added froma stock solution of dimethyl sulfoxide (DMSO). The final concentrationof DMSO in the differentiation medium does not exceed 0.1% (v/v). DMSO(0.1%) was added to the control cultures. The medium was replaced withmaintenance medium (DMEM supplemented with 5% of FBS and 100 ng/mL ofinsulin), and the cells cultured for 2 more days. Activity ofstimulation of adipogenesis was determined by exposure of the cells to[14-C]-acetic acid (7.4 kBq/mL), and uptake of [14-C]-acetic acidmonitored after 1 h of incubation. The medium is discarded and the cellswashed twice with phosphate-buffered saline. The cells are air-dried,and 200 mL of scintillation cocktail (Microscint-20, Packard) added tothe wells, and counted with a Packard TopCount microplate scintillationcounter. Stimulation of adipogenesis is expressed as concentrationsequivalent to the [14-C] label uptake counts in the treatment with 10 uMtelmisartan.

Example 3 Measurement of In Vivo Insulin-Sensitivity Activity

The hypoglycemic activity of the test compounds in insulin resistantobese fatty (fa/fa) Zucker rats (Jackson Laboratory, Bar Harbor, Me.).These rats are profoundly insulin resistant with extremely high bloodconcentrations of insulin. Lean littermates (−/−) are used as controls.Each test compounds is administered to three Zucker rats at 10 mg/kgdaily for five days after which blood samples are taken in thenon-fasting state. Blood samples are collected, placed in a hematocritcentrifuge tube, and centrifuged to obtain plasma. Insulin in thecollected plasma is measured by means of a radioimmuno-assay kit (LincoResearch, Inc, St Charles, Mo.). The insulin-sensitizing activity of thetest compounds are calculated as follows:

Insulin-sensitivity activity (%)=[(PI in C−PI in T)/PI in C]×100

-   -   where “PI in C” is plasma insulin in control rats and “PI in T”        is plasma insulin in rats treated with test compounds.

Example 4 A Clinical Trial Using a PPARgamma Activator to Treat Type 2Diabetes Without Causing Fluid Retention, Edema, or Heart Failure

A 49 year old female with hypertension, hypertriglyceridemia, and type 2diabetes was selected for therapy. Before administration of telmisartan,the patient had a blood pressure of 160/90 mmHg, fasting serum glucoseof 183 mg/dl, a fasting serum triglyceride level of 264 mg/dl, and anHDL cholesterol level of 48 mg/dl. The patient is taking anothermedication for type 2 diabetes but the dose of this medication is heldconstant throughout the trial. The patient is given telmisartan(Micardis®) at an oral dose of 80 mg/day. After three weeks oftelmisartan therapy, the blood pressure is reduced to 143/91 mmHg withlittle or no improvement in fasting glucose (188 mg/dl), triglyceride(281 mg/dl), or HDL cholesterol levels (50 mg/dl). The oral dose oftelmisartan (Micardis® is then increased to 160 mg/day. After sevenweeks of telmisartan (Micardis®) therapy at 160 mg/day, the patient'sblood pressure is reduced to 131/81 mmHg and there is a significantimprovement in the diabetes with the glucose level reduced to 145 mg/dl,the triglyceride level reduced to 178 mg/dl, and the HDL cholesterolincreased to 60 mg/dl. Clinical examination reveals no evidence of anyincrease in fluid retention, peripheral edema, pulmonary edema, orcongestive heart failure. The telmisartan (Micardis®) therapy iscontinued according to the judgment of the clinician in order tomaintain the improved control of the patient's blood pressure and hertype 2 diabetes.

Example 5 A Clinical Trial Using a PPARgamma Activator to Treat theMetabolic Syndrome Without Causing Fluid Retention, Edema, or HeartFailure

A 59 year old female with the metabolic syndrome was selected fortherapy. Before administration of telmisartan, the patient had a bloodpressure of 160/79 mmHg, fasting serum glucose of 118 mg/dl, fastinginsulin level of 15 microunits/ml, fasting triglycerides of 129 mg/dl,and waist girth of 120 cm. The patient has the metabolic syndrome asdefined by the National Cholesterol Education Program. The metabolicsyndrome is associated with a 5-9 fold increase in the risk fordeveloping type 2 diabetes and a 2-3 fold increase risk incardiovascular mortality. The patient is given telmisartan (Micardis®)at an oral dose of 80 mg/day for treatment of the metabolic syndrome.After two weeks of telmisartan therapy, the patient no longer meets thediagnostic criteria of the metabolic syndrome and her blood pressure isreduced to 130/69 mmHg, the fasting glucose is normalized to 105 mg/dl,and the fasting triglyceride level is reduced to 115 mg/dl. Clinicalexamination reveals no evidence of any increase in fluid retention,peripheral edema, pulmonary edema, or congestive heart failure. Thetelmisartan (Micardis®) therapy is continued according to the judgmentof the clinician in order to prevent recurrence of the metabolicsyndrome and prevent development of type 2 diabetes.

Example 6 A Clinical Trial Using a PPARgamma Activator to TreatInflammation Without Causing Fluid Retention, Edema or Heart Failure

A 57 year old female with osteoarthritis and inflammation as judged byelevated C-reactive protein (CRP) levels was selected for therapy.Before administration of telmisartan, the patient had a markedlyincreased serum CRP level of 7.9 mg/L indicative of active inflammation.The patient is given telmisartan (Micardis®) at an oral dose of 80mg/day. After 6 weeks of telmisartan therapy, the CRP level is reducedto 4.1 mg/L. After 9 weeks of therapy, the CRP level remains reduced at3.9 mg/L and symptoms of inflammation and osteoarthritis are stabilized.Clinical examination reveals no evidence of any increase in fluidretention, peripheral edema, pulmonary edema, or congestive heartfailure. The telmisartan (Micardis®) therapy is continued according tothe judgment of the clinician in order to maintain the improved controlof the inflammation.

REFERENCES

Examples of ARBs Encompassed by this Invention

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Examples of Insulin-Sensitizing Agents With Functionalities that can beUsed to Derivitize ARBs

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Anti-Inflammatory Effects of ARBs

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Methods claimed in this invention, in part, applies to natural orsynthetic PPAR ligands or activators, described in detail in thefollowing issued, allowed, pending or provisional patent applications:

33. U.S. Pat. No. 09/520,208 1,2-Dithiolane Derivatives, pending

34. U.S. Pat. No. 09/684,738 Novel Dithiolane Derivatives

35. U.S. Pat. No. 6,103,742 Pharmaceutical composition

36. U.S. Pat. No. 6,100,403 Production of benzaldehyde compounds

37. U.S. Pat. No. 6,087,385 Flavonoid derivatives

38. U.S. Pat. No. 6,087,384 Apoptosis inhibitor

39. U.S. Pat. No. 6,028,088 Flavonoid derivatives

40. U.S. Pat. No. RE36,575 Pyridine and thiazolidinedione derivatives

41. U.S. Pat. No. 6,022,897 Selective modulators of PPAR(and methods . ..

42. U.S. Pat. No. 6,011,036 Heterocyclic compounds having antidiabetic .. .

43. U.S. Pat. No. 6,011,031 Azolidinediones useful for the treatment ofdiabetes . . .

44. U.S. Pat. No. 6,008,237 Arylthiazolidinedione derivatives

45. U.S. Pat. No. 5,990,139 Thiazolidinedione derivatives or saltsthereof and . . .

46. U.S. Pat. No. 5,985,884 Heterocyclic compounds, process for theirpreparation . . .

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55. U.S. Pat. No. 5,939,442 Modulations of PPAR(, and methods for theuse thereof

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60. U.S. Pat. No. 5,902,726 Activators of the nuclear orphan receptorPPAR(

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69. U.S. Pat. No. 5,834,501 Heterocyclic compounds having anti-diabeticactivity . . .

70. U.S. Pat. No. 5,827,865 Heterocyclic compounds as pharmaceutical

71. U.S. Pat. No. 5,824,694 Thiazolidine derivatives for the treatmentof psoriasis

72. U.S. Pat. No. 5,811,439 Thiazolidinedione derivatives, method forpreparing . . .

73. U.S. Pat. No. 5,801,173 Heterocyclic compounds having antidiabetic .. .

74. U.S. Pat. No. 5,741,803 Substituted thiazolidinedionle derivatives

75. U.S. Pat. No. 5,693,651 Quinoline derivatives

76. U.S. Pat. No. 5,506,245 Thiazolidinedione compounds

77. U.S. Pat. No. 6,150,371 Method for preventing and for treatingautoimmune . . .

78. WO 01/12612 Benzoic acid derivatives for the treatment of diabetes .. .

79. WO 98/57941 New thiazolidinedione, oxazolidinedione . . .

80. WO 01/00603 Thiazole and oxazole derivatives . . .

81. WO 97/25042 Use of an antagonist of PPAR-alpha and PPAR-gamma . . .82. WO 98/05331 Prevention or treatment of type 2 diabetes orcardiovascular . . .

83. WO 97/28137 Heterocyclic derivatives as antidiabetic and antiobesity. . .

84. WO 00/27832 PPARγ ligands

85. WO 01/21602 Oxa- and thiazole derivatives . . .

86. WO 01/34094 Novel compounds to treat diabetes . . .

87. WO 99/62870 New 3-aryl-2-hydroxypropionic acid . . .

88. WO 99/62871 New 3-aryl-2-hydroxypropionic acid . . .

89. WO 99/62872 New 3-aryl-2-hydroxypropionic acid . . .

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The above-named patents contain the description of compounds that can beutilized in the practice of this invention. Consequently said compoundsare covered according to the claims of this invention.

All publications, patents and patent publications mentioned in thisspecification are herein incorporated by reference into thespecification in their entirety for all purposes.

Although the invention has been described with reference to preferredembodiments and examples thereof, the scope of the present invention isnot limited only to those described embodiments. As will be apparent topersons skilled in the art, modifications and adaptations to theabove-described invention can be made without departing from the spiritand scope of the invention, which is defined and circumscribed by theappended claims.

The foregoing is offered primarily for purposes of illustration. It willbe readily apparent to those of ordinary skill in the art that theoperating conditions, materials, procedural steps and other parametersof the invention described herein may be further modified or substitutedin various ways without departing from the spirit and scope of theinvention. For example, the invention has been described with humanpatients as the usual recipient, but veterinary use is alsocontemplated. Thus, the preceding description of the invention shouldnot be viewed as limiting but as merely exemplary.

1. A method for treating or limiting the rate of progression ofpolycystic kidney disease, comprising orally administering to a mammalin need thereof a therapeutically effective amount of a compoundsufficient to (a) at least partially activate peroxisome proliferatoractivated receptor-gamma (PPAR-gamma) and (b) at least partiallyinhibit, antagonize or block an activity of angiotensin II type 1receptors, wherein the therapeutically effective amount is about 20 mgto about 1000 mg.
 2. The method of claim 1 wherein the compound isadministered in a pharmaceutically acceptable form.
 3. The method ofclaim 1 wherein the compound is telmisartan or an analog thereof.
 4. Themethod of claim 1 wherein the polycystic kidney disease is autosomaldominant polycystic kidney disease and the compound is telmisartan. 5.The method of claim 1 wherein the compound is telmisartan and theeffective daily orally administered dose of telmisartan is about 80 mg.6. The method of claim 1 wherein the compound is telmisartan and theeffective daily orally administered dose of telmisartan is about 160 mg.7. The method of claim 1 wherein the compound is telmisartan and thetelmisartan is administered in combination with ramipril.
 8. The methodof claim 1 wherein the compound is telmisartan and the telmisartan isadministered in combination with lisinopril.
 9. The method of claim 7wherein 1 part by weight of telmisartan is administered in combinationwith 0.01 to 100 parts by weight of ramipril.
 10. The method of claim 8wherein 1 part by weight of telmisartan is administered in combinationwith 0.01 to 100 parts by weight of lisinopril.
 11. The method of claim9 wherein the telmisartan and the ramipril are administered as separatecompositions.
 12. The method of claim 9 wherein the telmisartan and theramipril are administered as a single composition. 13-17. (canceled) 18.An article of manufacture comprising a composition comprising 1 part byweight of telmisartan and a composition comprising 0.01 to 100 parts byweight of ramipril.
 19. The article of manufacture of claim 18 whereinthe telmisartan and the ramipril are in separate compositions.
 20. Thearticle of manufacture of claim 18 wherein the telmisartan and theramipril are in a single composition. 21-23. (canceled)
 24. A method fortreating or limiting the rate of progression of polycystic kidneydisease, comprising orally administering to an adult human in needthereof a therapeutically effective amount of telmisartan sufficient to(a) at least partially activate peroxisome proliferator activatedreceptor-gamma (PPAR-gamma) and (b) at least partially inhibit,antagonize or block an activity of angiotensin II type 1 receptors,wherein the therapeutically effective amount is about 20 mg to about1,000 mg.
 25. The method of claim 24, wherein the therapeuticallyeffective amount of telmisartan is about 80 mg or about 160 mg, andwherein the therapeutically effective amount of telmisartan isoptionally administered in combination with ramipril or lisinopril suchthat 1 part by weight of the telmisartan is optionally administered incombination with 0.01 to 100 parts by weight of ramipril or 0.01 to 100parts by weight of lisinopril.